TRPV1 vanilloid receptor antagonists with a bicyclic portion

ABSTRACT

The invention discloses compounds of formula I 
     
       
         
         
             
             
         
       
         
         
           
             wherein Y is a group of formula A, B, C, D, or E: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             and W, Q, n, R1, R2, R3, U1-U5, J and K have the meanings given in the description. 
           
         
       
    
     The compounds of formula I are TRPV1 antagonists and are useful as active ingredients of pharmaceutical compositions for the treatment of pain and other conditions ameliorated by the inhibition of the vanilloid receptor TRPV1.

This application is a U.S. national stage of PCT/EP2010/070538 filed onDec. 22, 2010, which claims priority to and the benefit of EuropeanApplication No. 10158292.2, filed on Mar. 30, 2010, the contents ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention concerns TRPV1 antagonists characterized by abicyclic portion and, when possible, pharmaceutically acceptable saltsthereof along with the formulations containing them. The pharmaceuticalcompositions of the invention are useful in the treatment of pain andother conditions ameliorated by the inhibition of the vanilloid receptorTRPV1.

BACKGROUND

The transient receptor potential vanilloid 1 (TRPV1) is a member of ionchannels mainly localized on primary afferent neurons. Activation ofTRPV1 on sensory neurons by chemical stimulants including capsaicin andresiniferatoxin, as well as low pH (<6), heat (>42° C.), and nucleosidessuch as ATP, leads to an influx of Ca²⁺ and Na⁺ ions through thechannel, causing depolarization of the cell and transmission of painfulstimuli. Unlike traditional analgesic drugs that either suppressinflammation (e.g. NSAIDs and COX-2 inhibitors) or block paintransmission (e.g. opiates), TRPV1 channel inhibitors aim to preventpain by blocking a receptor where pain is generated. In patients, theexpression of TRPV1 is up-regulated in a number of painful inflammatorydisorders. TRPV1 as a pain target has been validated by genetic deletionand pharmacological inhibition experiments. The pungency of capsaicinand many other agonists at the vanilloid receptor clearly defines TRPV1as a key transducer in the pain pathway. Characterization of TRPV1 mice,which lack both copies of the TRPV1 gene, shows a complete absence ofthermal hyperalgesia associated with inflammation demonstrating the keyrole of TRPV1 in disease and providing impetus to develop selectiveTRPV1 antagonists as a novel pain therapy with the potential for animproved side effect profile compared to existing therapies. Many novelselective and chemically distinct TRPV1 antagonists have been identifiedand a number of these have been assessed in preclinical models of pain.Some of them reverse mechanical hyperalgesia in the Freund's completeadjuvant model of inflammatory pain in rodents. Others show efficacy inneuropathic pain models, in post-operative pain and in cancer pain.These data provide robust validation of this approach for the treatmentof a broad range of pain conditions in humans.

In the bladder, the presence of TRPV1 was demonstrated in various celltypes, including urothelium, detrusor muscle and fibroblasts. There isgood evidence that TRPV1 in urothelium is functional. Capsaicin evokesan inward current similar to that seen in DRG neurons in patch-clampedhuman urothelial cells. Furthermore capsaicin induces calcium uptake inhuman urothelial cells culture which is blocked by the TRPV1 antagonistsimplying that the regulation of TRPV1 is similar in sensory neurons andurothelial cells. Overactive bladder (OAB) is a syndrome characterisedby urgency (with or without urge incontinence), usually with frequencyand nocturia, in the absence of other pathologic or metabolic conditionsthat might explain the symptoms. Differently from antimuscariniccompounds dominating the market of OAB that only act on the efferentcomponents, TRPV1 antagonists, acting on sensory nerves or onurothelium, are effective in diverse experimental models ofcystitis/overactive bladder without interfere with the physiologicalvolume-induced avoiding contractions (VIVC) and distention of theurinary bladder in healthy animals.

The documented ability of citric acid as well as pungent compounds suchas capsaicin to induce cough when delivered to the lungs of experimentalanimals and humans, combined with the contribution of TRPV1-sensitivenerves to airway hyper responsiveness and bronco constriction has led toa large degree of interest in the potential for targeting TRPV1 for thetreatment of a range of respiratory diseases. These effects are thoughtto derive from the key contribution of TRPV1 which is highly expressedby sensory neurons and vagal afferents that innervate the airways, tothe cough reflex. Preclinical studies have now demonstrated antitussiveefficacy of a range of TRPV1 antagonists in rodent models.

Dry Eye is a chronic dysfunction on tear and ocular surface epithelium.

Changes in corneal osmolarity is a trigger key event in cytokineproduction and ocular inflammation which are main causes of Dry Eye.

There are evidences that TRPV1 signal induces pro-inflammatory cytokinesecretion in the corneal epithelial cells and hyper osmolarity-inducedcytokine production is prevented by TRPV1 antagonists in cornealepithelial cells.

These data provide a strong rational for the systemic and topical use ofTRPV1 antagonists in the treatment of Dry Eye.

DESCRIPTION OF THE INVENTION

The present invention relates to TRPV1 inhibitors of formula (I)

wherein:

Y is a group of formula A, B, C, D, or E:

in which:

J and K are independently NH or O;

W is NH, O, a bond or CH₂;

Q is NH, O, a bond or CH₂;

n is 0 or 1;

U1, U2, U3, U4 and U5 form an aromatic ring and are independently CH, N,O, S, or one of them may be absent.

The aromatic ring is optionally substituted with one or both R1 and R2groups.

When one of U1-U5 is absent, the general formula I also includes mono orbi-substituted five membered heterocyclic rings (e.g. furan, imidazole,thiazole, triazole, oxazole, isoxazole, thiophene, pyrazole).

R1 and R2 are independently selected from hydrogen, halogen,trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis-(C₁-C₄)alkylamino, monocyclic ring system containing 0-4 heteroatomsindependently selected from N and O, which can be optionally substitutedby OH, phenyl, heterocycle, and wherein the alkyl chains of said(C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- or bis(C₁-C₄)alkylamino, can beoptionally substituted with an amino, mono- or bis-(C₁-C₄)alkylamino,morpholino, piperidino, pyrrolidino or piperazino group, provided thatthere are at least two carbon atoms between the nitrogen atom of saidgroup and the oxygen atom of the (C₁-C₄)alkoxy or the nitrogen atom ofsaid mono- or bis-(C₁-C₄)alkylamino.

R3 is hydrogen or with n=1 is CH₂ and forms a cycle with R1=CH₂ or═CH₂—CH₂.

With the proviso that when n is 0, Q is NH and W is a bond, then Y isdifferent from A or E, and with the exclusion of the compounds3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acid benzyl esterand benzyl (7-oxo)-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate.

The disclaimed compounds are known from Biorganic & Medicinal Chemistryletters, 17, (2007), 1302-1306, WO2008/126024 and WO2005/040100.

When one asymmetrical carbon is present in a compound of the formula(I), such a compound may exist in optically active form or in the formof mixtures of optical isomers, e.g. in the form of racemic mixtures.The present invention refers to all optical isomers and their mixtures,including the racemic mixtures.

According to a first preferred embodiment, the invention relates tocompounds of formula (IA), (IB) or (IC) wherein Y is A, C or E and W andQ are NH

J and K are independently NH or O;

n is 0 or 1;

U1, U2, U3, U4 and U5 form an aromatic ring and are independently CH, N,O, S, or one of them may be absent.

When one of U1-U5 is absent, the general formula IA also includes monoor bi-substituted five membered heterocycle rings (e.g. furan,imidazole, thiazole, triazole, oxazole, isoxazole, pyrazole).

R1 is as defined above, more preferably hydrogen, halogen,trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis-(C₁-C₄)alkylamino, heterocycle, monocyclic ring system containing0-4 heteroatoms independently selected from N and O, in particularpyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, and wherein the alkylchains of said (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis(C₁-C₄)alkylamino, can be optionally substituted with an amino, mono-or bis-(C₁-C₄)alkylamino, morpholino, piperidino, pyrrolidino orpiperazino group, provided that there are at least two carbon atomsbetween the nitrogen atom of said group and the oxygen atom of the(C₁-C₄)alkoxy or the nitrogen atom of said mono- orbis-(C₁-C₄)alkylamino.

R2 as defined above, is preferably halogen, trifluoromethyl,(C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- or bis-(C₁-C₄)alkylamino, monocyclicring system containing 0-4 heteroatoms independently selected from N andO, in particular pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, andwherein the alkyl chains of said (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis(C₁-C₄)alkylamino, can be optionally substituted with an amino, mono-or bis-(C₁-C₄)alkylamino, morpholino, piperidino, pyrrolidino orpiperazino group, provided that there are at least two carbon atomsbetween the nitrogen atom of said group and the oxygen atom of the(C₁-C₄)alkoxy or the nitrogen atom of said mono- orbis-(C₁-C₄)alkylamino.

R3, as defined above, is preferably hydrogen or when n=1 is CH₂ andforms a cycle with R1=CH₂.

Examples of compounds of formula IA are:

-   1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-morpholinobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-fluorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-chloro-2-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(2-(dimethylamino)-4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)-3-((pyridin-4-yl)methyl)urea-   1-((6-chloropyridin-3-yl)methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(4-chloro-2-(3-hydroxypyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(5-(trifluoromethyl-furan-2-yl)-methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea-   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea-   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea-   1-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[5-(trifluoromethyl)-2-pyridyl]methyl]urea-   1-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-[[2-isopropoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-[(4-tert-butylphenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-(1-piperidyl)-6-(trifluoromethyl)-3-pyridyl]methyl]urea-   1-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-[(4-tert-butyl-2-chloro-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-[(4-tert-butyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea-   1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-fluoro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-chloro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-(trifluoromethyl)-2-morpholinobenzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea-   1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea-   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea-   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea-   1-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea-   1-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea.

Examples of compounds of formula IB are:

-   1-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea-   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea-   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea.

Examples of compounds of formula IC are:

-   1-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-chlorobenzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-chloro-2-(dimethylamino)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-((6-chloropyridin-3-yl)methyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea-   1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea-   1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea)-   1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[2-(1-piperidyl)-6-(trifluoromethyl)-3-pyridyl]methyl]urea-   1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-(p-tolylmethyl)urea-   1-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[[2-methoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-pyridyl]methyl]urea-   1-[(2-isopropoxy-4-methyl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[(2-isopropoxy-6-methyl-3-pyridyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoro    methyl)-3-pyridyl]methyl]urea-   1-[[2-(imidazol-1-yl)-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[(4-tert-butylphenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[(4-methyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea-   1-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea.

According to a second preferred embodiment, the invention relates tocompounds of formula (ID), (1E) or (1F) wherein Y is A or B, W is NH, Qis a bond and R3 is hydrogen

J and K are independently NH or O;

n is 0 or 1;

R1 is hydrogen, halogen, trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,mono- or bis-(C₁-C₄)alkylamino, monocyclic ring system containing 0-4heteroatoms independently selected from N and O, in particularpyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, and wherein the alkylchains of said (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis(C₁-C₄)alkylamino, can be optionally substituted with an amino, mono-or bis-(C₁-C₄)alkylamino, morpholino, piperidino, pyrrolidino orpiperazino group, provided that there are at least two carbon atomsbetween the nitrogen atom of said group and the oxygen atom of the(C₁-C₄)alkoxy or the nitrogen atom of said mono- orbis-(C₁-C₄)alkylamino.

R2 is halogen, trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis-(C₁-C₄)alkylamino, monocyclic ring system containing 0-4 heteroatomsindependently selected from N and O, in particular pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, and wherein the alkyl chains of said(C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- or bis(C₁-C₄)alkylamino, can beoptionally substituted with an amino, mono- or bis-(C₁-C₄)alkylamino,morpholino, piperidino, pyrrolidino or piperazino group, provided thatthere are at least two carbon atoms between the nitrogen atom of saidgroup and the oxygen atom of the (C₁-C₄)alkoxy or the nitrogen atom ofsaid mono- or bis-(C₁-C₄)alkylamino.

The formula 1D and 1E substantially corresponds to formula I whereinU1=U2=U3=U4=U5 are CH.

Examples of compounds of formula ID-F are:

-   2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)acetamide-   2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)acetamide-   2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)acetamide-   2-(4-(trifluoromethyl)phenyl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)acetamide.

According to a third preferred embodiment, the invention relates tocompounds of formula (IG), (IH) or (IL) wherein Y is A, C or E, Q is NHand R3 is hydrogen

J and K are independently NH or O;

W is O or a bond;

n is 0 or 1.

R1 is hydrogen, halogen, trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,mono- or bis-(C₁-C₄)alkylamino, monocyclic ring system containing 0-4heteroatoms independently selected from N and O, in particularpyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, and wherein the alkylchains of said (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis(C₁-C₄)alkylamino, can be optionally substituted with an amino, mono-or bis-(C₁-C₄)alkylamino, morpholino, piperidino, pyrrolidino orpiperazino group, provided that there are at least two carbon atomsbetween the nitrogen atom of said group and the oxygen atom of the(C₁-C₄)alkoxy or the nitrogen atom of said mono- orbis-(C₁-C₄)alkylamino.

R2 is halogen, trifluoromethyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- orbis-(C₁-C₄)alkylamino, monocyclic ring system containing 0-4 heteroatomsindependently selected from N and O, in particular pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, and wherein the alkyl chains of said(C₁-C₄)alkyl, (C₁-C₄)alkoxy, mono- or bis(C₁-C₄)alkylamino, can beoptionally substituted with an amino, mono- or bis-(C₁-C₄)alkylamino,morpholino, piperidino, pyrrolidino or piperazino group, provided thatthere are at least two carbon atoms between the nitrogen atom of saidgroup and the oxygen atom of the (C₁-C₄)alkoxy or the nitrogen atom ofsaid mono- or bis-(C₁-C₄)alkylamino.

With the proviso that when n is 0, Q is NH and W is a bond, then Y isdifferent from A or E.

The formula IC substantially corresponds to formula I whereinU1=U2=U3=U4=U5 are CH.

Examples of compounds of formula IG-L are:

-   N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide-   N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide-   N-(4-(trifluoromethyl)-2-morpholinobenzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide-   N-(4-(trifluoromethyl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-5-carboxamide-   N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-5-carboxamide-   N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-8-carboxamide-   3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl    4-(trifluoromethyl)benzylcarbamate

The compounds of formula (IA), (IB) and (IC) are ureas that can beprepared by reaction of a compound of formula 1, 1′ or 1″, respectively,

wherein K and Y are as above defined, with a compound of formula 2

wherein R₁, R₂, R₃, U1, U2, U3, U4, U5 and n are as above defined andwhere one of 1, 1′, 1″ and 2, more commonly 2, is firstly converted intoisocyanate using triphosgene. Alternatively, N,N′-carbonyldimidazole(CDI) was used to form the uredyl derivative of one of the two aminesand which reacts with the other to give the desired urea. Compounds 1,1′, 1″ and 2 are prepared by standard procedures.

The compounds of formula (ID-L) are amides or carbamates that can beprepared by standard procedures.

In a further aspect of the present invention, compounds of formula Ibearing a solubilizing amine may be prepared in the form of apharmaceutically acceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula I will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude addition salts which may, for example, be formed by mixing asolution of the compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, nitric acid, maleic acid, citric acid, tartaric acid, phosphoricacid, p-toluenesulphonic acid, benzenesulphonic acid. Preferredpharmaceutically salts of the compounds of the present invention arethose with the inorganic acids.

The salts may be formed by conventional means, such as by reacting thefree base form of the suitable compounds of formula I with one or moreequivalents of the appropriate acid in a solvent or medium in which thesalt is insoluble or in a solvent such as water which is removed undervacuum.

Compositions of the Invention

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention that may beformulated together with one or more non-toxic pharmaceuticallyacceptable carriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), buccally or as an oral or nasal spray.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as, but not limited to, lactose,glucose and sucrose; starches such as, but not limited to, corn starchand potato starch; cellulose and its derivatives such as, but notlimited to, sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as, but not limited to, cocoa butter and suppository waxes; oilssuch as, but not limited to, peanut oil, cottonseed oil, safflower oil,sesame oil, olive oil, corn oil and soybean oil; glycols; such apropylene glycol; esters such as, but not limited to, ethyl oleate andethyl laurate; agar; buffering agents such as, but not limited to,magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other non-toxic compatible lubricants suchas, but not limited to, sodium lauryl sulfate and magnesium stearate, aswell as coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents that delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution, which in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions that are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragées, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient (s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals, which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants that may berequired. Ophthalmic formulations, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

In the treatment of painful conditions such as those listed below, asuitable indicated dosage level is about 0.1 mg to 2000 mg/day,preferably from about 5 mg to 1000 mg per day. The compounds may beadministered on a regimen of 1 to 3 times a day.

It will be appreciated that the amount of a compound of formula Irequired for use in any treatment will vary not only with the particularcompounds or compositions selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient.

The agents of invention are useful vanilloid receptor antagonists forthe treatment of pain of various genesis or aetiology and asanti-inflammatory agents for the treatment of inflammatory reactions,diseases or conditions. They are useful for the treatment ofinflammatory pain, for the treatment of hyperalgesia, and in particularfor the treatment of severe chronic pain. They are, for example, usefulfor the treatment of pain, inflammation consequential to trauma, e.g.associated with burns or subsequent to surgical intervention, e.g. aspost-operative analgesics, as well as for the treatment of inflammatorypain of diverse genesis, e.g. for the treatment of osteoarthritis andrheumatoid arthritis. They are suitable as analgesics for the treatmentof pain associated with, e.g. angina or cancer.

Other forms of pain associated with the activity of TRPV1 are headache,dental pain, pelvic pain, migraine, mastalgia and visceral pain. Thedisorders in which TRPV1 is involved are not limited to pain. Suchdiseases include: nerve-related diseases, e.g. neuropathies, nerveinjury and stroke; irritable bowel syndrome; gastrointestinal disorders,e.g. gastro-oesophageal reflux disease, Crohn's disease; respiratorydiseases, e.g. asthma, chronic obstructive pulmonary disease, cough;urinary incontinence; urinary bladder hypersensitiveness; skin diseases,e.g. psoriasis, dermatitis; cardiac diseases e.g. myocardial ischemia;hair growth related disorders e.g. hirsutism, alopecia; rhinitis;pancreatitis; vulvodynia; psychiatric disorders, e.g. anxiety or fear;obesity.

The compounds of the present invention have potent analgesic effect andpotential anti-inflammatory activity and their pharmaceuticallyformulations are thought to alleviate or to treat in particularneuropathic pain conditions such as diabetic neuropathy andpost-herpetic neuralgia, urinary incontinence and cough.

The compounds of the invention are also useful as active ingredients ofpharmaceutical compositions for the systemic and topical treatment ofDry Eye.

The invention will be now illustrated by means of the followingexamples.

EXAMPLES

All commercially available compounds were purchased from Vendors andwere used without further purification. Reaction courses were monitoredby thin-layer chromatography on silica gel (precoated F₂₅₄ Merckplates), the spots were examined with UV light and visualized withaqueous KMnO₄. Flash chromatography was performed using Merck silica gel(230-240 mesh). ¹H-NMR spectra were recorded on Varian 400 MHzspectrometer or Varian 200 MHz using TMS as internal standard. Massspectra were obtained with a Waters-Micromass ZMD spectrometer.

Example 11-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-nitro-1H-benzo[d]imidazol-2(3H)-one 4a (scheme 2)

To 3-nitro-1,2-phenylenediamine 3a (2 g, 13.06 mmol) dissolved in THF(50 ml) was added in one portion DCI (1.5 equiv., 19.6 mmol, 3.176 g)and the reaction was refluxed for 2 hours. (TLC AcOEt 1/petroleum ether1). The reaction was filtrated and the yellow solid material was washedwith THF and diethyl ether obtaining 2 g of the product that was usedfor the following step without further purification. Yield=88% ¹HNMR(DMSO, 200 MHz) δ 7.11 (1H, t, J=7.6 Hz), 7.31 (1H, dd, J=7.8 Hz, J′=1.2Hz), 7.74 (1H, dd, J=8.6 Hz, J′=1 Hz), 11.45 (2H, bs)

Preparation of 4-amino-1H-benzo[d]imidazol-2(3H)-one 1a (scheme 2)

To compound 4a (2 g, 11.6 mmol) dissolved in a mixture of 4/1 MeOH/THF(100 ml) was added C/Pd 10% (500 mg) and the reaction was hydrogenatedat 60 psi overnight. (TLC AcOEt 9/MeOH 1) The reaction was filtratedthrough a pad of Celite and the filtrate was evaporated under vacuum.The crude solid was crystallized from ether giving 1.5 g of a whitesolid. Yield=88%. ¹HNMR (DMSO, 200 MHz) δ 4.84 (2H, bs), 6.22 (2H, m),6.65 (1H, t, J=8 Hz), 9.98 (1H, bs), 10.33 (1H, bs)

Preparation of1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Commercially available 4-trifluoromethylbenzylamine (0.5 ml, 3.5 mmol)was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1 g, 3.5 mmol)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 5 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (5ml) of compound 1a (350 mg, 2.33 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent was evaporated andthe crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml)and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column gave 290 mg of a white solid. Yield=36% ¹HNMR(DMSO, 400 MHz) δ 4.40 (2H, d, J=6 Hz), 6.62 (1H, d, J=7.2 Hz), 6.84(2H, m), 6.96 (1H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.70 (2H, d, J=8.4Hz), 8.30 (1H, s), 9.99 (1H, bs), 10.60 (1H, bs); [M⁺¹] 351.1(C₁₆H₁₃F₃N₄O₂ requires 350.3).

Example 21-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Commercially available 2-fluoro-4-trifluoromethylbenzylamine (0.5 ml,3.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.12g, 3.7 mmol) was added to the solution. The mixture was warmed at 80° C.for 4 hours then evaporated and the residue was dissolved in 5 ml ofDMF. The solution of the isocyanate was added dropwise to a solution inDMF (5 ml) of compound 1a (360 mg, 2.4 mmol) and the mixture was warmedat 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent wasevaporated and the crude was dissolved in AcOEt (30 ml) and washed withwater (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 210 mg of a white solid.Yield=28% ¹HNMR (DMSO, 400 MHz) δ 4.42 (2H, d, J=6 Hz), 6.63 (1H, dd,J=8 Hz, J′=1.2 Hz), 6.85 (2H, m), 6.95 (1H, d, J=8 Hz), 7.62 (3H, m),8.35 (1H, bs), 9.99 (1H, bs), 10.61 (1H, bs); [M⁺¹] 369.1 (C₁₆H₁₂F₄N₄O₂requires 368.29).

Example 31-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Commercially available 2-chloro-4-trifluoromethylbenzylamine (700 mg,3.3 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (989mg, 3.3 mmol) was added to the solution. The mixture was warmed at 80°C. for 4 hours then evaporated and the residue was dissolved in 5 ml ofDMF. The solution of the isocyanate was added dropwise to a solution inDMF (5 ml) of compound 1a (319 mg, 2.14 mmol) and the mixture was warmedat 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent wasevaporated and the crude was dissolved in AcOEt (30 ml) and washed withwater (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 140 mg of a white solid.Yield=18% ¹HNMR (DMSO, 400 MHz) δ 4.44 (2H, d, J=5.6 Hz), 6.64 (1H, d,J=7.2 Hz), 6.84 (1H, t, J=8.4 Hz), 6.89 (1H, t), 6.96 (1H, d, J=8 Hz),7.64 (1H, d, J=8.4 Hz), 7.74 (1H, d), 7.86 (1H, s), 8.43 (1H, bs), 9.99(1H, bs), 10.61 (1H, bs); [M⁺¹] 385.0 (C₁₆H₁₂ClF₃N₄O₂ requires 384.74).

Example 41-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 2-(dimethylamino)-4-(trifluoromethyl)benzonitrile 14a(scheme 7)

To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (0.5ml, 3.6 mmol) dimethylamine (4 equiv., 0.95 ml) was added and thesolution was heated in closed vessel at 80° C. overnight. The reactionwas evaporated and the residue was dissolved in AcOEt and washed withwater and brine. The organic phase was evaporated obtaining 730 mg of apale yellow oil. Yield=94% ¹HNMR (CDCl₃, 200 MHz) δ 3.13 (6H, s), 7.05(1H, bs), 7.59 (1H, dd, J=8.4 Hz, J′=0.6 Hz), 7.99 (1H, bs)

Preparation of2-(aminomethyl)-5-(trifluoromethyl)-N,N-dimethyl-benzenamine 2a (scheme7)

Benzonitrile 14a (730 mg, 3.4 mmol) dissolved in 5 ml of ether was addeddropwise at 0° C. to LiAlH₄ (2 equiv., 260 mg) suspended in diethylether (40 ml). The mixture was stirred at room temperature for 24 hours.The reaction was quenched by addition of water and filtrated and thesalts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 720 mg of a yellow oil. Yield=97%¹HNMR (CDCl₃, 200 MHz) δ 2.78 (6H, s), 3.95 (2H, s), 7.36 (2H, m), 7.49(1H, d)

Preparation of1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2a (1.3 g, 5.9 mmol) was dissolved in 40 ml of AcOEt and at 0° C.triphosgene (1.75 g, 5.9 mmol) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (860 mg, 5.77 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (50 ml) andwashed with water (1×30 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 650 mg of a yellow solid.Yield=28% ¹HNMR (DMSO, 200 MHz) δ 2.51 (6H, bs), 4.43 (2H, d, J=5.6 Hz),6.62 (1H, dd, J=7.6 Hz, J′=1 Hz), 6.82 (2H, m), 6.97 (1H, dd, J=8 Hz,J′=1 Hz), 7.32 (1H, s), 7.39 (1H, d), 7.49 (1H, d), 8.35 (1H, bs), 9.99(1H, bs), 10.59 (1H, bs); [M⁺¹] 394.1 (C₁₈H₁₈F₃N₅O₂ requires 393.36).

Example 51-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzonitrile 14b(scheme 7)

To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (1ml, 7.2 mmol) pyrrolidine (4 equiv., 2.38 ml) was added and the solutionwas heated at 80° C. overnight. The reaction was evaporated and theresidue was dissolved in AcOEt and washed with water and brine. Theorganic phase was evaporated obtaining 940 mg of a yellow solid.Yield=54% ¹HNMR (DMSO, 200 MHz) δ 1.95 (4H, m), 3.58 (4H, m), 6.94 (2H,m), 7.73 (1H, dd, J=8 Hz, J′=0.8 Hz).

Preparation of(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)phenyl)-methanamine 2b

Benzonitrile 14b (940 mg, 3.9 mmol) dissolved in 5 ml of ether was addeddropwise at 0° C. to LiAlH₄ (2 equiv., 297 mg) suspended in diethylether (40 ml). The mixture was stirred at room temperature for 24 hours.The reaction was quenched by addition of water and filtrated and thesalts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 1 g of a yellow oil. Yield=99% ¹HNMR(DMSO, 200 MHz) δ 1.88 (4H, m), 3.17 (4H, m), 3.76 (2H, s), 7.00 ((1H,s), 7.14 (1H, m), 7.59 (1H, d, J=8.2 Hz)

Preparation of1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2b (0.5 ml, 2 mmol) was dissolved in 20 ml of AcOEt and at 0° C.triphosgene (580 mg, 2 mmol) was added to the solution. The mixture waswarmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (296 mg, 1.99 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH0.5). The solvent was evaporated and the crude was dissolved in AcOEt(30 ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 170 mgof a yellow solid. Yield=20% ¹HNMR (DMSO, 400 MHz) δ 1.91 (4H, bs), 3.22(4H, bs), 4.38 (2H, d, J=5.2 Hz), 6.62 (1H, d, J=8 Hz), 6.72 (1H, t),6.83 (1H, t), 6.95 (1H, d, J=8 Hz), 7.08 (1H, s), 7.18 (1H, d, J=7.6Hz), 7.45 (1H, d, J=7.6 Hz), 8.35 (1H, bs), 9.98 (1H, bs), 10.60 (1H,bs); [M⁺¹] 420.18 (C₂₀H₂₀F₃N₅O₂ requires 419.4).

Example 61-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(trifluoromethyl)-2-(piperidin-1-yl)benzonitrile 14c(scheme 7)

To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (1ml, 7.2 mmol) was added piperidine (4 equiv., 2.8 ml) and the solutionwas heated at 80° C. overnight. The reaction was evaporated and theresidue was dissolved in AcOEt and washed with water and brine. Theorganic phase was evaporated obtaining 1 g of a yellow oil. Yield=56%¹HNMR (DMSO, 200 MHz) δ 1.60 (6H, m), 3.20 (4H, m), 7.34 (2H, m), 7.89(1H, dd, J=8.6 Hz, J′=0.4 Hz)

Preparation of(4-(trifluoromethyl)-2-(piperidin-1-yl)phenyl)-methanamine 2c

Benzonitrile 14c (1 g, 4 mmol) dissolved in 5 ml of ether was addeddropwise at 0° C. to LiAlH₄ (2 equiv., 305 mg) suspended in diethylether (40 ml). The mixture was stirred at room temperature for 24 hours.The reaction was quenched by addition of water and filtrated and thesalts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 980 mg of a yellow oil. Yield=95%¹HNMR (DMSO, 200 MHz) δ 1.57 (6H, m), 1.80 (2H, bs), 2.81 (4H, m), 3.78(2H, s), 7.23 (1H, s), 7.35 (1H, d, J=7.8 Hz), 7.70 (1H, d, J=8.2 Hz)

Preparation of1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2c (500 mg, 1.9 mmol) was dissolved in 20 ml of AcOEt and at 0° C.triphosgene (580 mg, 2 mmol) was added to the solution. The mixture waswarmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (265 mg, 1.78 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH0.5). The solvent was evaporated and the crude was dissolved in AcOEt(30 ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 140 mgof a pale yellow solid. Yield=18% ¹HNMR (DMSO, 400 MHz) δ 1.54 (2H, m),1.68 (4H, m), 2.85 (4H, m), 4.42 (2H, d, J=6 Hz), 6.63 (1H, d, J=7.6Hz), 6.76 (1H, t), 6.84 (1H, t, J=8.4 Hz), 6.95 (1H, d, J=8.4 Hz), 7.31(1H, s), 7.41 (1H, d), 7.52 (1H, d, J=8.4 Hz), 8.33 (1H, s), 10.01 (1H,bs), 10.60 (1H, bs); [M⁺¹] 434.11 (C₂₁H₂₂F₃N₅O₂ requires 433.43).

Example 71-(4-(trifluoromethyl)-2-(4-morpholino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(trifluoromethyl)-2-(4-morpholino)benzonitrile 14d(scheme 7)

To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (4ml, 29 mmol) morpholine (4 equiv., 10 ml) was added and the solution washeated at 80° C. overnight. The reaction was evaporated and the residuewas dissolved in AcOEt and washed with water and brine. The organicphase was evaporated obtaining 6.19 g of a yellow oil. Yield=83% ¹HNMR(DMSO, 200 MHz) δ 3.24 (4H, m), 3.75 (4H, m), 7.94 (1H, m), 8.23 (1H,m).

Preparation of (4-(trifluoromethyl)-2-(4-morpholino)phenyl)methanamine2d

Benzonitrile 14d (6.19 g, 24.2 mmol) dissolved in 15 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 1.83 g) suspended indiethyl ether (60 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 5.3 g of a yellow oil. Yield=84% ¹HNMR(DMSO, 200 MHz) δ 2.88 (4H, m), 3.20 (2H, bs), 3.72 (4H, m), 3.77 (2H,s), 7.27 (1H, s), 7.38 (1H, dd, J=7.8 Hz, J′=1 Hz), 7.72 (1H, d, J=8 Hz)

Preparation of1-(4-(trifluoromethyl)-2-(4-morpholino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2d (300 mg, 1.15 mmol) was dissolved in 20 ml of AcOEt and at 0°C. triphosgene (350 mg, 1 equiv.) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (200 mg, 1.3 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH0.5). The solvent was evaporated and the crude was dissolved in AcOEt(30 ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 100 mgof a pale yellow solid. Yield=20% ¹HNMR (DMSO, 200 MHz) δ 2.91 (4H, m),3.76 (4H, m), 4.44 (2H, d, J=5.6 Hz), 6.63 (1H, d, J=7.6 Hz), 6.88 (3H,m), 7.64 (1H, d, J=8.2 Hz), 7.73 (1H, d), 7.85 (1H, bs), 8.44 (1H, bs),9.99 (1H, bs), 10.60 (1H, bs); [M⁺¹] 436.2 (C₂₀H₂₀F₃N₅O₃ requires435.4).

Example 81-(4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile14e (scheme 7)

To commercially available 2-chloro-4-trifluoromethylbenzonitrile 13 (1ml, 7.2 mmol) in DMF 1 equiv. of NaH and 1,2,4-tetrazole (4 equiv., 1.98g) were added and the mixture was heated at 80° C. overnight. Thereaction was evaporated and the residue was dissolved in AcOEt andwashed with water and brine. The organic phase was evaporated obtaining900 mg of a yellow solid. Yield=53% ¹HNMR (DMSO, 200 MHz) δ 8.08 (1H,dd, J=7.6 Hz, J′=1 Hz), 8.33 (3H, m), 9.29 (1H, s).

Preparation of(4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)-methanamine 2e

Benzonitrile 14e (860 mg, 3.6 mmol) dissolved in 5 ml of ether was addeddropwise at 0° C. to LiAlH₄ (2 equiv., 276 mg) suspended in diethylether (20 ml). The mixture was stirred at room temperature for 24 hours.The reaction was quenched by addition of water and filtrated and thesalts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 600 mg of a red oil. Yield=70% ¹HNMR(DMSO, 200 MHz) δ 3.31 (2H, bs), 3.64 (2H, s), 7.85 (3H, m), 8.28 (1H,s), 9.02 (1H, s).

Preparation of1-(4-(trifluoromethyl)-2-(1H-1,2,4-triazol-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2e (600 mg, 2.48 mmol) was dissolved in 20 ml of AcOEt and at 0°C. triphosgene (755 mg, 1 equiv.) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 10 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (450 mg, 3 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH0.5). The solvent was evaporated and the crude was dissolved in AcOEt(30 ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 110 mgof an orange solid. Yield=10% ¹HNMR (DMSO, 200 MHz) δ 4.30 (2H, d, J=6Hz), 6.64 (1H, dd, J=7.4 Hz, J′=1.2 Hz), 6.79 (2H, m), 6.91 (1H, dd),7.83 (1H, d), 7.92 (2H, d), 8.33 (1H, bs), 8.42 (1H, bs), 9.07 (1H, bs),9.94 (1H, bs), 10.59 (1H, bs); [M⁺¹] 418.2 (C₁₈H₁₄F₃N₇O₂ requires417.34).

Example 91-(4-fluorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of1-(4-fluorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Commercially available p-fluorobenzylamine (0.76 ml, 6.7 mmol) wasdissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.98 g, 1 equiv.)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 20 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (900 mg, 6 mmol) and the mixture was warmed at 80° C.for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 420 mg of a white solid. Yield=23% ¹HNMR (DMSO, 200 MHz) δ 4.29(2H, d, J=6 Hz), 6.62 (1H, dd, J=7.6 Hz, J′=1.2 Hz), 6.80 (2H, m), 6.95(1H, dd, J=8.2 Hz, J′=1.2 Hz), 7.15 (2H, m), 7.35 (2H, m), 8.23 (1H,bs), 9.96 (1H, bs), 10.59 (1H, bs); [M⁺¹] 301.1 (C₁₅H₁₃FN₄O₂ requires300.29).

Example 101-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of1-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Commercially available p-chlorobenzylamine (846 mg, 6 mmol) wasdissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.78 g, 1 equiv.)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 20 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (900 mg, 6 mmol) and the mixture was warmed at 80° C.for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 300 mg of a white solid. Yield=16% ¹HNMR (DMSO, 200 MHz) δ 4.30(2H, d, J=6.2 Hz), 6.62 (1H, dd, J=7.6 Hz, J′=1.2 Hz), 6.83 (2H, m),6.96 (1H, dd, J=8 Hz, J′=1 Hz), 7.35 (4H, m), 8.27 (1H, bs), 9.98 (1H,bs), 10.59 (1H, bs); [M⁺¹] 317.1 (C₁₅H₁₃ClN₄O₂ requires 316.74).

Example 111-(4-chloro-2-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-chloro-2-(dimethylamino)benzonitrile 16af (scheme 8)

To commercially available 2-fluoro-4-chlorobenzonitrile 15a (2 g, 12.8mmol) dimethylamine (4 equiv., 3.5 ml) was added and the solution washeated in closed vessel at 80° C. overnight. The reaction was evaporatedand the residue was dissolved in AcOEt and washed with water and brine.The residue was purified by chromatographic column using EtOAc1/petroleum ether 9 as eluant obtaining 1.95 g of a transparent oil.Yield=87% ¹HNMR (DMSO, 200 MHz) δ 3.01 (6H, s), 6.91 (1H, dd, J=8.4 Hz,J′=2 Hz), 7.02 (1H, d, J=2 Hz), 7.60 (1H, d, J=8.4 Hz)

Preparation of 2-(aminomethyl)-5-chloro-N,N-dimethylbenzenamine 2af

Benzonitrile 16af (1.95 g, 10.8 mmol) dissolved in 5 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 821 mg) suspended indiethyl ether (20 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 2 g of a pale yellow oil. Yield=98%¹HNMR (DMSO, 200 MHz) δ 1.72 (2H, bs), 2.61 (6H, s), 3.71 (2H, s), 6.99(1H, m), 7.05 (1H, d, J=2.2 Hz), 7.46 (1H, d, J=8 Hz)

Preparation of1-(4-chloro-2-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2af (1 g, 5.5 mmol) was dissolved in 20 ml of AcOEt and at 0° C.triphosgene (1.63 g, 1 equiv.) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 10 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (820 mg, 5.5 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 550 mg of a white solid.Yield=28% ¹HNMR (DMSO, 200 MHz) δ 2.64 (6H, s), 4.34 (2H, d, J=5.8 Hz),6.62 (1H, dd, J=7.2 Hz, J′=1 Hz), 6.73 (1H, t), 6.83 (1H, t, J=7.6 Hz),6.90 (1H, dd, J=8.2 Hz, J′=1 Hz), 7.06 (2H, m), 7.31 (1H, d, J=8.8 Hz),8.33 (1H, bs), 9.98 (1H, bs), 10.59 (1H, bs); [M⁺¹] 360.7 (C₁₇H₁₈ClN₅O₂requires 359.81).

Example 121-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-chloro-2-(pyrrolidin-1-yl)benzonitrile 16ag (scheme 8)

To commercially available 2-fluoro-4-chlorobenzonitrile 15a (3 g, 19.3mmol) pyrrolidine (4 equiv., 6.38 ml) was added and the solution washeated at 80° C. overnight. The reaction was evaporated and the residuewas dissolved in AcOEt and washed with water and brine. The residue waspurified by crystallization from water obtaining 3.86 g of a pale yellowsolid. Yield=97% ¹HNMR (DMSO, 200 MHz) δ 1.93 (4H, m), 3.51 (4H, m),6.69 (1H, dd, J=8.4 Hz, J′=1.8 Hz), 6.76 (1H, d, J=2 Hz), 7.49 (1H, d,J=8.4 Hz)

Preparation of (4-chloro-2-(pyrrolidin-1-yl)phenyl)methanamine 2ag

Benzonitrile 16ag (3.8 g, 18.4 mmol) dissolved in 15 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 1.4 g) suspended in diethylether (30 ml). The mixture was stirred at room temperature for 24 hours.The reaction was quenched by addition of water and filtrated and thesalts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 4 g of a yellow oil. Yield=98% ¹HNMR(DMSO, 200 MHz) δ 1.72 (2H, bs), 1.86 (4H, m), 3.14 (4H, m), 3.68 (2H,s), 6.77 (1H, d, J=2 Hz), 6.80 (1H, dd, J=8.2 Hz), 7.36 (1H, d, J=8 Hz)

Preparation of1-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2ag (1 g, 4.76 mmol) was dissolved in 20 ml of AcOEt and at 0° C.triphosgene (1.4 g, 1 equiv.) was added to the solution. The mixture waswarmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 10 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (700 mg, 4.9 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 360 mg of a white solid.Yield=19% ¹HNMR (DMSO, 200 MHz) δ 1.89 (4H, m), 3.17 (4H, m), 4.30 (2H,d, J=5.4 Hz), 6.61 (1H, dd, J=7.6 Hz, J′=1 Hz), 6.69 (1H, t), 6.87 (4H,m), 7.24 (1H, d, J=7.8 Hz), 8.38 (1H, bs), 10.00 (1H, bs), 10.59 (1H,bs); [M⁺¹] 386.7 (C₁₉H₂₀ClN₅O₂ requires 385.85).

Example 131-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Preparation of 4-chloro-2-(piperidin-1-yl)benzonitrile 16ah (scheme 8)

To commercially available 2-fluoro-4-chlorobenzonitrile 15a (2.2 g,12.87 mmol) piperidine (4 equiv., 5.6 ml) was added and the solution washeated at 80° C. overnight. The reaction was evaporated and to theresidue water was added and the solid material was filtrated, washedwith water and dried obtaining 3 g of a pale yellow solid. Yield=97%¹HNMR (DMSO, 200 MHz) δ 1.54 (2H, m), 1.65 (4H, m), 3.14 (4H, m), 7.09(1H, dd, J=8.2 Hz, J′=2 Hz), 7.14 (1H, m), 7.69 (1H, d, J=8.4 Hz)

Preparation of (4-chloro-2-(piperidin-1-yl)phenyl)methanamine 2ah

Benzonitrile 16ah (3 g, 13.6 mmol) dissolved in 20 ml of ether was addeddropwise at 0° C. to LiAlH₄ (2 equiv., 1.03 g) suspended in diethylether (30 ml). The mixture was stirred at room temperature for 24 hours.The reaction was quenched by addition of water and filtrated and thesalts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 2.92 g of a yellow oil. Yield=96%¹HNMR (DMSO, 200 MHz) δ 1.52 (2H, m), 1.61 (4H, m), 2.23 (2H, bs), 2.76(4H, m), 3.69 (2H, s), 6.97 (1H, d, J=2.2 Hz), 7.04 (1H, dd, J=8.2 Hz,J′=2.2 Hz), 7.46 (1H, d, J=8 Hz)

Preparation of1-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2ah (1.34 g, 6 mmol) was dissolved in 20 ml of AcOEt and at 0° C.triphosgene (1.78 g, 1 equiv.) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 10 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (900 mg, 6 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (50 ml) andwashed with water (1×40 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 750 mg of a white solid.Yield=31% ¹HNMR (DMSO, 200 MHz) δ 1.58 (2H, m), 1.66 (4H, m), 2.78 (4H,M), 4.32 (2H, d, J=6 Hz), 6.63 (1H, dd), 6.73 (1H, t), 6.94 (1H, t),6.95 (1H, dd), 7.06 (2H, m), 7.29 (1H, d), 8.35 (1H, bs), 10.05 (1H,bs), 10.60 (1H, bs); [M⁺¹] 400.2 (C₂₀H₂₂ClN₅O₂ requires 399.87)

Example 141-(4-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of compound 4-(aminomethyl)-N,N-dimethylbenzenamine 2i(scheme 9)

Commercially available 4-dimethylaminobenzonitrile 18i (2 g, 13.7 mmol)dissolved in 15 ml of ether was added dropwise at 0° C. to LiAlH₄ (2equiv., 1 g) suspended in diethyl ether (40 ml). The mixture was stirredat room temperature for 24 hours. The reaction was quenched by additionof water and filtrated and the salts were washed with ether. The organicphase was separated, anhydrified and evaporated giving 1.85 g of a paleyellow oil. Yield=90% ¹HNMR (DMSO, 200 MHz) δ 1.60 (2H, bs), 2.84 (6H,s), 3.57 (2H, s), 6.67 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.6 Hz)

Preparation of1-(4-(dimethylamino)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

4-(aminomethyl)-N,N-dimethylbenzenamine 2i (1 g, 6.9 mmol) was dissolvedin 40 ml of AcOEt and at 0° C. triphosgene (2 g, 1 equiv.) was added tothe solution. The mixture was warmed at 80° C. for 4 hours thenevaporated and the residue was dissolved in 20 ml of DMF. The solutionof the isocyanate was added dropwise to a solution in DMF (10 ml) ofcompound 1a (1 g, 6.9 mmol) and the mixture was warmed at 80° C. for 8hours. (TLC AcOEt). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 350 mg of a white solid. Yield=16% ¹HNMR (DMSO, 200 MHz) δ 2.51(6H, s), 4.18 (2H, d, J=5.6 Hz), 6.58 (2H, m), 6.69 (2H, d, J=8.8 Hz),6.86 (2H, m), 7.14 (2H, d, J=8.8 Hz), 8.18 (1H, s), 9.98 (1H, bs), 10.58(1H, bs); [M⁺¹] 326.5 (C₁₇H₁₉N₅O₂ requires 325.37).

Example 151-(4-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(pyrrolidin-1-yl)benzonitrile 18l (scheme 9)

To commercially available 4-chlorobenzonitrile 17 (5 g, 36 mmol) 12 mlof pyrrolidine were added and the reaction was heated at 100° C. for 24hours in closed vessel. The reaction was evaporated and the residue wasdissolved in AcOEt and washed with water and brine. The purification ofthe crude residue by chromatographic column using AcOEt 1/Petroleumether 9 as eluant gave 1.68 g of a pale yellow solid. Yield=33% ¹HNMR(DMSO, 200 MHz) δ 1.96 (4H, m), 3.28 (4H, m), 6.58 (2H, d, J=9 Hz), 7.51(2H, d, J=9 Hz)

Preparation of (4-(pyrrolidin-1-yl)phenyl)methanamine 2l

Benzonitrile 18l (1.68 g, 9.76 mmol) dissolved in 10 ml of ether wasadded drop wise at 0° C. to LiAlH₄ (2 equiv., 742 mg) suspended indiethyl ether (40 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 1.48 g of a yellow oil. Yield=86%¹HNMR (DMSO, 200 MHz) δ 1.60 (2H, bs), 1.93 (4H, m), 3.17 (4H, m), 3.57(2H, s), 6.46 (2H, d, J=8.6 Hz), 7.09 (2H, d, J=8.4 Hz).

Preparation of1-(4-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

(4-(pyrrolidin-1-yl)phenyl)methanamine 2l (774 mg, 4.4 mmol) wasdissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.3 g, 1 equiv.)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 20 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (660 mg, 4.4 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent was evaporated andthe crude was dissolved in AcOEt (50 ml) and washed with water (1×30 ml)and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column gave 250 mg of a white solid. Yield=16% ¹HNMR(DMSO, 200 MHz) δ 1.92 (4H, m), 3.17 (4H, m), 4.17 (2H, d, J=5.6 Hz),6.58 (4H, m), 6.84 (2H, m), 7.12 (2H, d, J=8.6 Hz), 8.16 (1H, bs), 9.93(1H, bs), 10.58 (1H, bs); [M⁺¹] 352.3 (C₁₉H₂₁N₅O₂ requires 351.4).

Example 161-(4-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(piperidin-1-yl)benzonitrile 18m (scheme 9)

To commercially available 4-chlorobenzonitrile 17 (1 g, 7.26 mmol) 3 mlof piperidine were added and the reaction was heated at 100° C. for 72hours in closed vessel. The reaction was evaporated and the residue wasdissolved in AcOEt and washed with water and brine. The purification ofthe crude residue by chromatographic column using AcOEt 1/Petroleumether 9 as eluant gave 1.2 g of a pale yellow oil. Yield=89% ¹HNMR(DMSO, 200 MHz) δ 1.57 (6H, m), 3.34 (4H, m), 6.98 (2H, d, J=9 Hz), 7.53(2H, d, J=9 Hz)

Preparation of (4-(piperidin-1-yl)phenyl)methanamine 2m

Benzonitrile 18m (1.2 g, 6.48 mmol) dissolved in 10 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 493 mg) suspended indiethyl ether (40 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 1 g of an orange oil. Yield=82%. ¹HNMR(DMSO, 200 MHz) δ 1.57 (6H, m), 3.06 (4H, m), 3.58 (2H, s), 6.84 (2H, d,J=8.6 Hz), 7.13 (2H, d, J=8.4 Hz), 7.33 (2H, bs).

Preparation of1-(4-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

(4-(piperidin-1-yl)phenyl)methanamine 2m (1.47 g, 7.8 mmol) wasdissolved in 40 ml of AcOEt and at 0° C. triphosgene (2.3 g, 1 equiv.)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 20 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (1.15 g, 7.8 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crudewas dissolved in AcOEt (50 ml) and washed with water (1×30 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by chromatographiccolumn gave 520 mg of a pale yellow solid. Yield=18% ¹HNMR (DMSO, 200MHz) δ 1.58 (6H, m), 3.08 (4H, m), 4.19 (2H, d, J=6 Hz), 6.62 (2H, m),6.86 (4H, m), 7.15 (2H, d, J=8.8 Hz), 8.19 (1H, bs), 9.95 (1H, bs),10.58 (1H, bs); [M⁺¹] 366.3 (C₂₀H₂₃N₅O₂ requires 365.43).

Example 171-(4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of1-(4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Commercially available p-methylbenzylamine (0.88 ml, 6.97 mmol) wasdissolved in 40 ml of AcOEt and at 0° C. triphosgene (2 g, 1 equiv.) wasadded to the solution. The mixture was warmed at 80° C. for 4 hours thenevaporated and the residue was dissolved in 20 ml of DMF. The solutionof the isocyanate was added drop wise to a solution in DMF (10 ml) ofcompound 1a (1 g, 6.97 mmol) and the mixture was warmed at 80° C. for 8hours. (TLC AcOEt). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 350 mg of a white solid. Yield=17% ¹HNMR (DMSO, 200 MHz) δ 6.61(1H, dd, J=7.6 Hz, J′=1.2 Hz), 6.70 (1H, t), 6.83 (1H, t, J=8 Hz), 6.92(1H, dd, J=8 Hz, J′=1 Hz), 7.17 (4H, dd, J=15.6 Hz, J′=8.2 Hz), 8.22(1H, bs), 9.96 (1H, bs), 10.58 (1H, bs); [M⁺¹] 297.1 (C₁₆H₁₆N₄O₂requires 296.32).

Example 181-(2-(dimethylamino)-4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1) ù

Preparation of 4-methyl-2-dimethylaminobenzonitrile 16bf (scheme 8)

To commercially available 2-fluoro-4-methylbenzonitrile 15b (2.5 g, 18.5mmol) was added dimethylamine (4 equiv., 4.8 ml) and the solution washeated at 80° C. overnight. The reaction was evaporated and the residuewas dissolved in AcOEt and washed with water and brine. The organicphase was evaporated obtaining 2.96 g of a yellow oil. Yield=99% ¹HNMR(DMSO, 200 MHz) δ 2.31 (3H, s), 2.93 (6H, s), 6.74 (1H, dd, J=8 Hz,J′=0.8 Hz), 6.85 (1H, s), 7.47 (1H, d, J=8 Hz)

Preparation of (4-methyl-2-dimethylaminophenyl)methanamine 2bf

Benzonitrile 16bf (2.9 g, 18.1 mmol) dissolved in 25 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 1.38 g) suspended indiethyl ether (40 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 2.35 g of an oil. Yield=80% ¹HNMR(DMSO, 200 MHz) δ 2.65 (2H, bs), 2.25 (3H, s), 2.60 (6H, s), 3.70 (2H,s), 6.80 (2H, m), 7.27 (1H, d, J=7.4 Hz)

Preparation1-(2-(dimethylamino)-4-methylbenzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2bf (1.1 g, 6.7 mmol) was dissolved in 40 ml of AcOEt and at 0° C.triphosgene (1.93 g, 6.7 mmol) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 15 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (1 g, 6.7 mmol) andthe mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5).The solvent was evaporated and the crude was dissolved in AcOEt (50 ml)and washed with water (1×30 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude residue by chromatographic column gave 450 mg of a pale yellowsolid. Yield=19% ¹HNMR (DMSO, 200 MHz) δ 2.26 (3H, s), 2.59 (6H, m),4.33 (2H, d, J=5.6 Hz), 6.60 (2H, m), 6.87 (4H, m), 7.18 (1H, d, J=7.6Hz), 8.28 (1H, s), 9.96 (1H, bs), 10.60 (1H, bs); [M⁺¹] 339.56(C₁₈H₂₁N₅O₂ requires 339.39).

Example 191-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-(methyl)-2-(piperidin-1-yl)benzonitrile 16bh (scheme 8)

To commercially available 2-fluoro-4-methylbenzonitrile 15b (2.5 g, 18.5mmol) was added piperidine (4 equiv., 7.3 ml) and the solution washeated at 80° C. overnight. The reaction was evaporated and the residuewas dissolved in AcOEt and washed with water and brine. The organicphase was evaporated obtaining 2.3 g of a white solid. Yield=65% ¹HNMR(DMSO, 200 MHz) δ 1.62 (6H, m), 2.32 (3H, s), 3.07 (4H, m), 6.87 (1H,dd, J=7.8 Hz, J′=0.8 Hz), 6.95 (1H, s), 7.53 (1H, d, J=7.8 Hz)

Preparation of (4-(methyl)-2-(piperidin-1-yl)phenyl)methanamine 2bh

Benzonitrile 16bh (2.3 g, 11.5 mmol) dissolved in 15 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 873 mg) suspended indiethyl ether (40 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 2.25 g of an oil. Yield=96% ¹HNMR(DMSO, 200 MHz) δ 1.59 (6H, m), 2.24 (3H, s), 2.76 (4H, m), 3.67 (2H,s), 6.80 (2H, m), 7.27 (1H, d, J=8.4 Hz)

Preparation of1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Amine 2bh (1.1 g, 5.4 mmol) was dissolved in 40 ml of AcOEt and at 0° C.triphosgene (1.56 g, 5.4 mmol) was added to the solution. The mixturewas warmed at 80° C. for 4 hours then evaporated and the residue wasdissolved in 15 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1a (1 g, 6.7 mmol) andthe mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5).The solvent was evaporated and the crude was dissolved in AcOEt (50 ml)and washed with water (1×30 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude residue by chromatographic column gave 450 mg of a whitesolid. Yield=22% ¹HNMR (DMSO, 200 MHz) δ 1.58 (6H, m), 2.78 (4H, m),4.34 (2H, d, J=5.8 Hz), 6.59 (2H, m), 6.90 (4H, m), 7.18 (1H, d, J=7.6Hz), 8.26 (1H, s), 10.01 (1H, bs), 10.60 (1H, bs); [M⁺¹] 379.51(C₂₁H₂₅N₅O₂ requires 379.46).

Example 201-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)-3-((pyridin-4-yl)methyl)urea(scheme 1)

Preparation of1-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)-3-((pyridin-4-yl)methyl)urea

Commercially available 4-aminomethylpyridine (2 g, 20.8 mmol) wasdissolved in 60 ml of AcOEt and at 0° C. triphosgene (5.8 g, 21 mmol)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 20 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (3.16 g, 21 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent was evaporated andthe crude was dissolved in AcOEt (80 ml) and washed with water (1×40 ml)and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column gave 640 mg of a white solid. Yield=11% ¹HNMR(DMSO, 200 MHz) δ 4.34 (2H, d, J=5.8 Hz), 6.62 (1H, dd, J=7.6 Hz, J′=1Hz), 6.92 (3H, m), 7.31 (2H, dd, J=4.4 Hz, J′=1.4 Hz), 8.49 (3H, m),10.03 (1H, bs), 10.59 (1H, bs); [M⁺¹] 284.1 (C₁₄H₁₃N₅O₂ requires283.29).

Example 211-((6-chloropyridin-3-yl)methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of1-(((6-chloropyridin-3-yl)methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

Commercially available (6-chloropyridin-3-yl)methanamine (1 g, 7 mmol)was dissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.93 g, 7mmol) was added to the solution. The mixture was warmed at 80° C. for 4hours then evaporated and the residue was dissolved in 10 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (1 g, 6.7 mmol) and the mixture was warmed at 80° C.for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent was evaporated andthe crude was dissolved in AcOEt (80 ml) and washed with water (1×40 ml)and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column gave 450 mg of a pale yellow solid. Yield=21%¹HNMR (DMSO, 200 MHz) δ 4.32 (2H, d, J=5.8 Hz), 6.62 (1H, d, J=7.2 Hz),6.85 (3H, m), 7.48 (1H, d, J=8.4 Hz), 7.81 (1H, dd, J=8.2 Hz, J′=2.4Hz), 8.33 (2H, m), 10.02 (1H, bs), 10.60 (1H, bs); [M⁺¹] 317.8(C₁₄H₁₂ClN₅O₂ requires 317.73).

Example 221-(4-chloro-2-(3-hydroxypyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of 4-chloro-2-(3-hydroxypyrrolidin-1-yl)benzonitrile 16ai(scheme 8)

To commercially available 2-fluoro-4-chlorobenzonitrile 15a (1 g, 6.4mmol) was added 3-pyrrolidin 1-ol (2 equiv., 1 g) and the solution washeated at 80° C. overnight. The reaction was evaporated and the residuewas dissolved in AcOEt and washed with water and brine. The organicphase was evaporated obtaining 1.2 g of a white solid. Yield=85% ¹HNMR(DMSO, 200 MHz) δ 1.91 (2H, m), 3.54 (4H, m), 4.37 (1H, b), 5.06 (1H,bd, J=3.4 Hz), 6.72 (2H, m), 7.50 (1H, d, J=8.2 Hz)

Preparation of 1-(2-(aminomethyl)-5-chlorophenyl)pyrrolidin-3-ol 2ai

Benzonitrile 16ai (1.2 g, 5.4 mmol) dissolved in 15 ml of ether wasadded dropwise at 0° C. to LiAlH₄ (2 equiv., 410 mg) suspended indiethyl ether (40 ml). The mixture was stirred at room temperature for24 hours. The reaction was quenched by addition of water and filtratedand the salts were washed with ether. The organic phase was separated,anhydrified and evaporated giving 1.18 g of an oil. Yield=96% ¹HNMR(DMSO, 200 MHz) δ 1.90 (2H, m), 3.34 (4H, m), 3.67 (2H, s), 4.27 (1H,b), 4.90 (1H, b), 6.76 (2H, m), 7.34 (1H, d, J=8 Hz)

Preparation of1-(4-chloro-2-(3-hydroxypyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

1-(2-(aminomethyl)-5-chlorophenyl)pyrrolidin-3-ol 2ai (1.18 g, 5.2 mmol)was dissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.4 g, 5.2mmol) was added to the solution. The mixture was warmed at 80° C. for 4hours then evaporated and the residue was dissolved in 10 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1a (674 mg, 4.52 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 8/MeOH 2). The solvent was evaporated and thecrude was dissolved in AcOEt (80 ml) and washed with water (1×40 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by chromatographiccolumn gave 390 mg of a pale pink solid. Yield=21% ¹HNMR (DMSO, 200 MHz)δ 2.20 (2H, m), 3.33 (4H, m), 3.69 (2H, s), 4.29 (1H, b), 5.20 (1H, b),6.62 (2H, m), 6.90 (4H, m), 7.27 (1H, d, J=8 Hz), 8.29 (1H, s), 9.95(1H, bs), 10.60 (1H, bs); [M⁺¹] 402.4 (C₁₉H₂₀ClN₅O₃ requires 401.85).

Example 231-(5-(trifluoromethyl-furan-2-yl)-methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea(scheme 1)

Preparation of1-(5-(trifluoromethyl-furan-2-yl)-methyl)-3-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)urea

a) Procedure Using Triphosgene

Commercially available 2-(aminomethyl)-5-(trifluoromethyl)furan (1 ml,7.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (2.20g, 7.7 mmol) was added to the solution. The mixture was warmed at 80° C.for 4 hours then evaporated and the residue was dissolved in 5 ml ofDMF. The solution of the isocyanate was added drop wise to a solution inDMF (5 ml) of compound 1a (720 mg, 4.8 mmol) and the mixture was warmedat 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and thecrude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by chromatographiccolumn gave 780 mg of a white solid. Yield=29% ¹HNMR (DMSO, 400 MHz) δ4.38 (2H, d, J=6 Hz), 6.51 (d, 1H, J=2), 6.64 (d, 1H), 6.85 (m, 2H),6.87 (m, 1H), 7.15 (m, 1H), 8.30 (s, 1H), 9.97 (s, 1H), 10.60 (s, 1H);[M⁺¹] 340.5 (C₁₄H₁₁F₄N₄O₃ requires 340.26).

b) Procedure Using CDI

To a solution of 2-aminomethyl-5-trifluoromethylfurane (1 g, 6.1 mmol)in THF (30 mL) was added CDI (2.1 mol eq) and the mixture was heated at70° C. overnight. The reaction mixture was evaporated, water was addedand the aqueous phase was extracted with EtOAc (3×20 mL). The recombinedorganic phases were anhydrified over Na₂SO₄ and evaporated at reducedpressure. The oil obtained (1.6 g, 5.9 mmol) was dissolved in DMF (30mL) and the bicyclic amine 1a was added (0.8 mol eq), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by crystallization from amixture of MeOH/EtOAc to obtain the title compound as white solid (0.78g, 2.3 mmol, 30% Yield). ¹HNMR (DMSO, 200 MHz) δ 4.38 (d, 2H, J=6); 6.49(d, 1H, J=4), 6.51 (dd, 1H), 6.85 (m, 2H), 6.94 (dd, 1H), 7.16 (m, 1H),8.03 (s, 1H), 9.97 (bs, 1H), 10.60 (bs, 1H). [M⁺¹] 340.26 (C₁₄H₁₁F₃N₄O₃requires 340.21).

Example 241-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of 4-nitrobenzo[d]oxazol-2(3H)-one 4b (scheme 2)

To 2-amino-3-nitrophenol 3b (2 g, 13.00 mmol) dissolved in THF (50 ml)was added in one portion DCI (1.5 equiv., 19.6 mmol, 3.176 g) and thereaction was refluxed for 4 hours. (TLC AcOEt 1/petroleum ether 1). Thereaction was evaporated and the crude material was dissolved in HCL 2Nand extracted 3 times with chloroform. The combined organic phases werewashed with water, brine, dried over sodium sulfate and concentratedunder vacuum. The crude solid was crystallized from ether giving 1.5 gof a beige solid. Yield=65% ¹HNMR (DMSO, 200 MHz) δ 7.27 (1H, t, J=7.8Hz), 7.72 (1H, dd, J=8.2 Hz, J′=1 Hz), 7.93 (1H, dd, J=8.4 Hz, J′=0.6Hz), 12.64 (1H, bs)

Preparation of 4-aminobenzo[d]oxazol-2(3H)-one 1b (scheme 2)

To compound 4b (1 g, 5.72 mmol) dissolved in a mixture of 4/1 MeOH/THF(50 ml) C/Pd 10% (250 mg) was added and the reaction was hydrogenated at60 psi overnight. (TLC AcOEt) The reaction was filtrated through a padof Celite and the filtrate was evaporated under vacuum. The crude solidwas crystallized from ether giving 476 mg of a white solid. Yield=55.5%.¹HNMR (DMSO, 200 MHz) δ 5.07 (2H, bs), 6.47 (2H, m), 6.79 (1H, t, J=8Hz), 10.93 (1H, bs)

Preparation of1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Commercially available 4-trifluoromethylbenzylamine (0.5 ml, 3.5 mmol)was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1 g, 3.5 mmol)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 5 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (5ml) of compound 1b (350 mg, 2.33 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent was evaporated andthe crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml)and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column gave 200 mg of a white solid. Yield=24% ¹HNMR(DMSO, 400 MHz) δ 4.41 (2H, d, J=6 Hz), 6.98 (3H, m), 7.05 (1H, m), 7.55(2H, d), 7.70 (2H, d, J=8 Hz), 8.49 (1H, bs), 11.00 (1H, bs); [M⁺¹]352.1 (C₁₆H₁₂F₃N₃O₃ requires 351.28).

Example 251-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of1-(2-fluoro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Commercially available 2-fluoro-4-trifluoromethylbenzylamine (0.5 ml,3.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.12g, 3.7 mmol) was added to the solution. The mixture was warmed at 80° C.for 4 hours then evaporated and the residue was dissolved in 5 ml ofDMF. The solution of the isocyanate was added drop wise to a solution inDMF (5 ml) of compound 1b (360 mg, 2.4 mmol) and the mixture was warmedat 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and thecrude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by chromatographiccolumn gave 100 mg of a white solid. Yield=11% ¹HNMR (DMSO, 400 MHz) δ4.43 (2H, d, J=6 Hz), 6.99 (3H, m), 7.05 (1H, m), 7.62 (3H, m), 8.53(1H, bs), 10.98 (1H, bs); [M⁺¹] 370.1 (C₁₆H₁₁F₄N₃O₃ requires 369.27).

Example 261-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of1-(2-chloro-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Commercially available 2-chloro-4-trifluoromethylbenzylamine (572 mg,2.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (809mg, 2.7 mmol) was added to the solution. The mixture was warmed at 80°C. for 4 hours then evaporated and dissolved in 5 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (5ml) of compound 1b (270 mg, 1.8 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crudewas dissolved in AcOEt (30 ml) and washed with water (1×20 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by chromatographiccolumn gave 70 mg of a white solid. Yield=10% ¹HNMR (DMSO, 400 MHz) δ4.45 (2H, d, J=6 Hz), 6.97 (2H, d, J=4.4 Hz), 7.07 (2H, m), 7.63 (1H, d,J=8 Hz), 7.74 (2H, d), 7.86 (1H, s), 8.61 (1H, bs), 10.90 (1H, bs);[M⁺¹] 386.6 (C₁₆H₁₁ClF₃N₃O₃ requires 385.7).

Example 271-(4-fluoro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of1-(4-fluoro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Commercially available 4-fluoro-2-trifluoromethylbenzylamine (0.5 ml,3.7 mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.12g, 3.7 mmol) was added to the solution. The mixture was warmed at 80° C.for 4 hours then evaporated and the residue was dissolved in 5 ml ofDMF. The solution of the isocyanate was added dropwise to a solution inDMF (5 ml) of compound 1b (360 mg, 2.4 mmol) and the mixture was warmedat 80° C. for 8 hours. (TLC AcOEt 4/petroleum ether 6). The solvent wasevaporated and the crude was dissolved in AcOEt (30 ml) and washed withwater (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 90 mg of a white solid. Yield=10%¹HNMR (DMSO, 200 MHz) δ 4.36 (2H, d, J=5.6 Hz), 6.71 (1H, t, J=6 Hz),6.98 (2H, m), 7.56 (4H, m), 8.55 (1H, bs), 11.09 (1H, bs); [M⁺¹] 370.2(C₁₆H₁₁F₄N₃O₃ requires 369.27).

Example 281-(4-chloro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)ureascheme 1)

Preparation of1-(4-chloro-2-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Commercially available 4-chloro-2-trifluoromethylbenzylamine (1 g, 4.77mmol) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.41 g,4.77 mmol) was added to the solution. The mixture was warmed at 80° C.for 4 hours then evaporated and the residue was dissolved in 5 ml ofDMF. The solution of the isocyanate was added dropwise to a solution inDMF (5 ml) of compound 1b (475 mg, 3.2 mmol) and the mixture was warmedat 80° C. for 8 hours. (TLC AcOEt 4/petroleum ether 6). The solvent wasevaporated and the crude was dissolved in AcOEt (30 ml) and washed withwater (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 120 mg of a white solid.Yield=9.7% ¹HNMR (DMSO, 200 MHz) δ 4.45 (2H, d, J=5.6 Hz), 6.99 (4H, m),7.65 (1H, d), 7.73 (1H, d), 7.85 (1H, bs), 8.62 (1H, bs), 11.04 (1H,bs); [M⁺¹] 386.6 (C₁₆H₁₁ClF₃N₃O₃ requires 385.73).

Example 291-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)ureascheme 1)

Preparation of1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Amine 2a (1.2 g, 5.5 mmol) (Scheme 7) was dissolved in 40 ml of AcOEtand at 0° C. triphosgene (1.63 g, 5.5 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1b (820 mg, 5.5mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt7/petroleum ether 3). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 300 mg of a white solid. Yield=14% ¹HNMR (DMSO, 200 MHz) δ 2.51(6H, s), 4.71 (2H, d, J=5.6 Hz), 6.55 (2H, d, J=8.2 Hz), 7.05 (1H, t,J=7.6 Hz), 7.40 (1H, m), 7.51 (1H, d), 10.06 (1H, bt), 11.53 (1H, bs),11.80 (1H, bs); [M⁺¹] 395.1 (C₁₈H₁₇F₃N₄O₃ requires 394.35).

Example 301-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Amine 2b (289 mg, 1.2 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (356 mg, 1.2 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1b (180 mg, 1.2mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 100 mg of a white solid.Yield=20% ¹HNMR (DMSO, 200 MHz) δ 1.94 (4H, m), 3.23 (4H, m), 4.67 (2H,d, J=5.6 Hz), 6.55 (2H, dd, J=8.8 Hz, J′=1.2 Hz), 7.05 (1H, t, J=8.2Hz), 7.17 (2H, d, J=7.2 Hz), 7.46 (1H, d), 9.98 (1H, t), 11.53 (1H, bs),11.80 (1H, bs); [M⁺¹] 421.2 (C₂₀H₁₉F₃N₄O₃ requires 420.39).

Example 311-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Amine 2c (350 mg, 1.33 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (395 mg, 1.33 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated anddissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1b (100 mg, 0.66 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 40 mg of a white solid.Yield=14% ¹HNMR (DMSO, 400 MHz) δ 1.55 (2H, m), 1.68 (4H, m), 2.85 (4H,m), 4.43 (2H, d, J=5.6 Hz), 6.88 (1H, t), 6.98 (2H, m), 7.05 (1H, m),7.31 (1H, s), 7.42 (1H, d), 7.52 (1H, d, J=8 Hz), 8.52 (1H, s), 11.00(1H, bs); [M⁺¹] 435.3 (C₂₁H₂₁F₃N₄O₃ requires 434.41).

Example 321-(4-(trifluoromethyl)-2-(4-morpholino)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(4-morpholino)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Amine 2d (362 mg, 3.8 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (1.12 g, 1 equiv.) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1b (384 mg, 2.56mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 200 mg of a pale rosesolid. Yield=18% ¹HNMR (DMSO, 400 MHz) δ 2.91 (4H, m), 3.76 (4H, m),4.46 (2H, d, J=5.6 Hz), 6.97 (3H, m), 7.05 (1H, m), 7.36 (1H, s), 7.46(1H, d), 7.54 (1H, d), 8.53 (1H, s), 11.00 (1H, bs); [M⁺¹] 437.1(C₂₀H₁₉F₃N₄O₄ requires 436.4).

Example 331-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea (scheme1)

Preparation of1-(4-chlorobenzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)urea

Commercially available p-chlorobenzylamine (1.6 g, 11.4 mmol) wasdissolved in 60 ml of AcOEt and at 0° C. triphosgene (3.38 g, 1 equiv.)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 30 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1b (1.7 g, 11.4 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 7/petroleum ether 3). The solvent wasevaporated and the crude was dissolved in AcOEt (80 ml) and washed withwater (1×50 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 500 mg of a white solid.Yield=14% ¹HNMR (DMSO, 200 MHz) δ 4.57 (2H, d, J=5.8 Hz), 6.53 (2H, m),7.04 (1H, m), 7.41 (4H, s), 9.88 (1H, t), 11.53 (1H, s), 11.80 (1H, bs);[M⁺¹] 318.5 (C₁₅H₁₂ClN₃O₃ requires 317.73).

Example 341-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea(scheme 1)

Preparation of 5-chloro-7-nitrobenzo[d]oxazol-2(3H)-one 6 (Scheme 3)

DCI (36.4 mmol, 5.9 g) was added in one portion to2-amino-4-chloro-6-nitrophenol 5 (5 g, 26.5 mmol) suspended in AcOEt(150 ml) and the reaction was stirred vigorously for 2 hours. 100 ml ofwater were added to the reaction and then the organic phase waseliminated by evaporation. HCl 20% was added (20 ml) and the resultingsolid material was filtered and washed with HCl 1N, cold water, MeOH andether obtaining 5.6 g of a beige solid. Yield=98% ¹HNMR (DMSO, 200 MHz)δ 7.59 (1H, d, J=2.2 Hz), 7.86 (1H, d, J=2.2 Hz), 12.56 (1H, bs)

Preparation of 7-aminobenzo[d]oxazol-2(3H)-one 1c (Scheme 3)

To compound 6 (4 g, 18.56 mmol) dissolved in a mixture of 4/1 MeOH/DMF(50 ml) C/Pd 10% (500 mg) was added and the reaction was hydrogenated at60 psi overnight. (TLC AcOEt 3/petroleum ether 7) The reaction wasfiltrated through a pad of Celite and the filtrate was evaporated undervacuum. The crude solid was crystallized from ether giving 2.8 g of abeige solid. Yield=99%. ¹HNMR (DMSO, 200 MHz) δ 5.31 (2H, bs), 6.26 (1H,dd, J=7.6 Hz, J′=1 Hz), 6.38 (1H, dd, J=8.4 Hz, J′=1.2 Hz), 6.80 (1H, t,J=8 Hz), 11.32 (1H, bs)

Preparation of1-(4-(trifluoromethyl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea

Commercially available 4-trifluoromethylbenzylamine (1 ml, 7 mmol) wasdissolved in 20 ml of AcOEt and at 0° C. triphosgene (2 g, 7 mmol) wasadded to the solution. The mixture was warmed at 80° C. for 4 hours thenevaporated and the residue was dissolved in 5 ml of DMF. The solution ofthe isocyanate was added dropwise to a solution in DMF (10 ml) ofcompound 1c (700 mg, 4.66 mmol) and the mixture was warmed at 80° C. for8 hours. (TLC AcOEt 4/petroleum ether 6). The solvent was evaporated andthe crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml)and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column gave 320 mg of a white solid. Yield=19.5% ¹HNMR(DMSO, 400 MHz) δ 4.41 (2H, d, J=6 Hz), 6.67 (1H, dd, J=7.6 Hz, J′=1.2Hz), 7.00 (1H, t, J=8 Hz), 7.09 (1H, t), 7.51 (2H, d, J=8 Hz), 7.70 (3H,m), 8.73 (1H, s), 10.60 (1H, bs); [M⁺¹] 352.1 (C₁₆H₁₂F₃N₃O₃ requires351.3).

Example 351-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea

Amine 2b (795 mg, 3.3 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (979 mg, 3.3 mmol) was added to the solution.

The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1c (330 mg, 2.2mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt1/petroleum ether 1). The solvent was evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 240 mg of a white solid. Yield=26% ¹HNMR (DMSO, 200 MHz) δ 1.91(4H, m), 3.22 (4H, m), 4.38 (2H, d, J=5.4 Hz), 6.66 (1H, dd, J=7.6 Hz,J′=1.2 Hz), 7.00 (3H, m), 7.19 (1H, d, J=8 Hz), 7.39 (1H, d), 7.72 (1H,dd, J=8.6 Hz, J′=1), 8.72 (1H, bs), 11.63 (1H, bs); [M⁺¹] 421.3(C₂₀H₁₉F₃N₄O₃ requires 420.4).

Example 361-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)urea

Amine 2c (1 g, 3.8 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt andat 0° C. triphosgene (1.13 g, 3.8 mmol) was added to the solution. Themixture was warmed at 80° C. for 4 hours then evaporated and the residuewas dissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1c (390 mg, 2.6 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt1/petroleumether 1). The solvent was evaporated and the crude was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 160 mgof a white solid. Yield=14% ¹HNMR (DMSO, 200 MHz) δ 1.56 (2H, bs), 1.69(4H, bs), 2.85 (4H, m), 4.42 (2H, d, J=5.6 Hz), 6.66 (1H, dd, J=8 Hz,J′=0.8 Hz), 7.01 (2H, m), 7.32 (1H, s), 7.44 (2H, dd, J=7.6 Hz), 7.72(1H, dd, J=8.6 Hz, J′=1 Hz), 8.73 (1H, bs), 11.68 (1H, bs); [M⁺¹] 435.2(C₂₁H₂₁F₃N₄O₃ requires 434.4).

Example 371-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea

Preparation of1-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea

To a solution of [6-(trifluoromethyl)-3-pyridyl)]-methanamine (1 g, 4.7mmol) in THF (30 mL) was added CDI (2.1 mol eq) and the mixture washeated at 70° C. overnight. The reaction mixture was evaporated, waterwas added and the aqueous phase was extracted with EtOAc (3×20 mL). Therecombined organic phases were anhydrified over Na₂SO₄ and evaporated atreduced pressure (quantitative yield). The oil obtained (0.34 g, 1.2mmol) was dissolved in DMF (15 mL) and the bicyclic amine 1c (Scheme 3)was added (0.8 mol eq), then the mixture obtained was heated at 100° C.overnight. The solvent was removed at reduced pressure and the residuewas purified by chromatography (1:1 EtOAc:petroleum ether) to obtain theproduct as a white solid (0.064 g, 20% Yield). ¹HNMR (DMSO, 200 MHz) δ4.46 (d, 2H, J=6), 6.66 (d, 1H, J=8), 6.96 (t, 1H), 7.04 (bt, 1H), 7.64(d, 1H, J=8), 7.86 (m, 2H), 8.70 (s, 1H), 8.77 (s, 1H), 11.60 (bs, 1H).[M⁺¹] 358.02 (C₁₅H₁₁F₃N₄O₃ requires 357.27).

Example 381-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea

Preparation of1-(2-oxo-3H-1,3-benzoxazol-7-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea

To a solution of 2-aminomethyl-5-trifluoromethylfurane (1 g, 6.1 mmol)in THF (30 mL) was added CDI (2.1 mol eq) and the mixture was heated at70° C. overnight. The reaction mixture was evaporated, water was addedand the aqueous phase was extracted with EtOAc (3×20 mL). The recombinedorganic phases were anhydrified over Na₂SO₄ and evaporated at reducedpressure (1.6 g, 5.9 mmol). The oil obtained (0.31 g, 1.19 mmol) wasdissolved in DMF (20 mL) and the bicyclic amine 1c (Scheme 3) was added(0.8 mol eq, 0.15 g), then the mixture obtained was heated at 100° C.overnight. The solvent was removed at reduced pressure and the residuewas purified by chromatography (100% EtOAc) to obtain the product aswhite solid (0.05 g, 13% Yield). ¹HNMR (DMSO, 200 MHz) δ 4.37 (d, 2H,J=6), 6.48 (d, 1H, J=2), 6.70 (dd, 1H), 7.01 (m, 2H), 7.16 (m, 1H), 7.70(dd, 1H, J=2), 8.69 (s, 1H), 11.62 (bs, 1H). [M⁺¹] 341.61 (C₁₄H₁₀F₃N₃O₄requires 341.24).

Example 391-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea

Preparation of2-(1-pyrrolidin)-6-(trifluoromethyl)-pyridine-3-carbonitrile 28e (Scheme14)

To 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) wasadded pyrrolidine (4 mol eq) and the mixture was heated in neat at 90°C. for 3 h. The mixture was concentrated, water was added and themixture was extracted with EtOAc (3×20 mL). The recombined organicphases were anhydrified and evaporated to dryness to obtain2-(1-pyrrolidin)-6-(trifluoromethyl)nicotinonitrile as pale yellow oil(0.88 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.44 (m, 4H), 2.10(m, 4H), 7.25 (d, 1H, J=8), 7.54 (d, 1H).

Preparation of2-(1-pyrrolidin)-6-(trifluoromethyl)-3-aminomethyl-pyridine 29e

The nitrile 28e (0.88 g) was added in small portion to a mixture ofLiAlH₄ (0.26 g, 2 mol eq) in Et₂O (30 mL) stirred at 0° C. Then themixture was stirred at room temperature overnight. The excess of LiAlH₄was decomposed by water addition at 0° C., the solid formed wasfiltered, washed with Et₂O and the filtrate was separated. The organicphase was anhydrified over Na₂SO₄ and evaporated to dryness to obtain29e as pale yellow oil (0.58 g, 2.3 mmol, 70% Yield) used withoutfurther purification.

Preparation of1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea

To a solution of2-(1-pyrrolidinyl)-6-(trifluoromethyl)-3-aminomethyl-pyridine 29e (0.58g, 2.3 mmol) in THF (25 mL) was added CDI (2.1 mol eq, 0.77 g) and themixture was heated for 5 h. The reaction mixture was evaporated, waterwas added and the aqueous phase was extracted with EtOAc (3×20 mL). Therecombined organic phases were anhydrified over Na₂SO₄ and evaporated atreduced pressure. The oil obtained (0.9 g, 2.25 mmol) was dissolved inDMF (20 mL) and the bicyclic amine 1a was added (0.8 mol eq, 0.31 g),then the mixture obtained was heated at 100° C. overnight. The solventwas removed at reduced pressure and the residue was purified bychromatography (9.5:0.5 EtoAc:MeOH) to obtain the product as a paleyellow solid (0.1 g, 0.25 mmol, 12% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.89(m, 4H), 3.56 (m, 4H), 4.43 (d, 2H, J=6), 6.60 (dd, 1H), 6.64 (t, 1H),6.73 (t, 1H), 6.79 (d, 1H), 7.13 (d, 1H, J=6), 7.72 (d, 1H, J=8), 7.95(s, 1H), 8.31 (s, 1H), 9.97 (bs, 1H), 10.60 (bs, 1H). [M⁺¹] 421.10(C₁₉H₁₉F₃N₆O₂ requires 420.39).

Example 401-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of 2-(1-piperidyl)-6-methyl-pyridine-3-carbonitrile 32b(Scheme 16)

To 2-chloro-6-methyl-3-pyridine carbonitrile (1 g, 6.5 mmol) was addedpiperidine (2.56 mL, 4 mol eq) and the mixture was heated in neat at 90°C. for 4 h. The mixture was concentrated, water was added and themixture was extracted with EtOAc (3×20 mL). The recombined organicphases were anhydrified and evaporated to dryness to obtain 32b as paleyellow oil (1.28 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.54(m, 6H), 2.16 (m, 4H), 3.11 (s, 3H), 7.28 (d, 1H, J=8), 7.64 (d, 1H).

Preparation of [6-methyl-2-(1-piperidyl)-3-pyridyl]methanamine 33b

The nitrile 32b (1.44 g, 7.1 mmol)) was added in small portion to amixture of LiAlH₄ (0.55 g, 2 mol eq) in Et₂O (30 mL) stirred at 0° C.Then the mixture was stirred at room temperature overnight. The excessof LiAlH₄ was decomposed by water addition at 0° C., the solid formedwas filtered, washed with Et₂O and the filtrate was separated. Theorganic phase was anhydrified over Na₂SO₄ and evaporated to dryness toobtain 33b as yellow oil (1.06 g, 5.18 mmol, 74% Yield) used withoutfurther purification.

Preparation of1-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 33b (1.06 g, 5.18 mmol) in THF (20 mL) was added CDI(2.1 mol eq, 1.76 g) and the mixture was heated for 6 h. The reactionmixture was evaporated, water was added and the aqueous phase wasextracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure. The oilobtained (1.04 g, 3.36 mmol) was dissolved in DMF (20 mL) and thebicyclic amine 1a was added (0.8 mol eq, 0.40 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by chromatography (100%EtoAc)) to obtain the product as a pale yellow solid (0.30 g, 0.78 mmol,31% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.63 (m, 6H), 2.34 (s, 3H), 2.95 (m,4H), 4.26 (d, 2H, J=6), 6.60 (m, 2H), 6.87-6.93 (m, 3H), 7.54 (d, 1H,J=8), 8.28 (s, 1H), 9.99 (bs, 1H), 10.59 (bs, 1H). [M⁺¹] 381.5(C₂₀H₂₄N₆O₂ requires 380.44).

Example 411-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[5-(trifluoromethyl)-2-pyridyl]methyl]urea

To a solution of triphosgene (0.148 g, 0.37 mol eq) in anh. CH₂Cl₂ (10mL) was slowly added the amine 1a (0.2 g, 1.34 mmol) solubilized inCH₂Cl₂ (10 mL) and DIEA (2.2 mol eq, 0.5 mL). After the addition wascompleted, the reaction mixture was stirred at room temp. for 15 min.Then the [5-(trifluoromethyl)-2-pyridyl]methanamine (1 mol eq, 0.23 g)solubilized in CH₂Cl₂ (10 mL) and DIEA (2.2 mol eq, 0.5 mL) was added inone portion. The mixture obtained was stirred at room temp. for 12 h.The solvent was removed at reduced pressure, water was added and themixture was extracted with EtOAc (3×20 mL). The recombined organicphases were anhydrified over sodium sulfate and evaporated to dryness.The residue was purified by chromatography (9.5:0.5 EtoAc:MeOH) toobtain the product as yellow solid (0.075 g, 0.22 mmol, 16% Yield).¹HNMR (DMSO, 400 MHz) δ 4.35 (d, 2H, J=6), 6.22 (t, 1H, J=4), 6.65 (d,1H, J=6), 6.88 (m, 2H), 7.63 (d, 1H, J=8), 8.21 (dd, 1H), 8.48 (s, 1H),8.91 (m, 1H), 9.99 (bs, 1H), 10.60 (bs, 1H). [M⁺¹] 351.60 (C₁₅H₁₂F₃N₅O₂requires 351.28).

Example 421-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea(scheme 1)

Preparation of 5-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one 11 (scheme 5)

To a solution of 2-amino-3-nitrophenol (4.62 g, 30 mmol) in DMF (20 ml)ethylbromoacetate (3.3 ml, 30 mmol) and K₂CO₃ (4.56 g, 33 mmol) wereadded and the reaction was stirred at room temperature for 20 hours. Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by crystallization from ether/hexane gave 4.65 g of ayellow solid. Yield: 80%. ¹HNMR (DMSO, 200 MHz) δ 4.74 (2H, s), 7.15(1H, t, J=8.4 Hz), 7.41 (1H, dd, J=8.2 Hz, J′=1.6 Hz), 7.77 (1H, dd,J=8.4 Hz, J′=1.2 Hz), 10.38 (1H, bs)

Preparation of 5-amino-2H-benzo[b][1,4]oxazin-3(4H)-one 1e

To compound 11 (2.3 g, 11.85 mmol) dissolved in a mixture of 4/1MeOH/THF (50 ml) C/Pd 10% (500 mg) was added and the reaction washydrogenated at 60 psi overnight. (TLC AcOEt 3/petroleum ether 7) Thereaction was filtrated through a pad of Celite and the filtrate wasevaporated under vacuum. The crude solid was crystallized from ethergiving 1.75 g of a beige solid. Yield=90%. ¹HNMR (DMSO, 200 MHz) δ 4.44(2H, s), 6.18 (1H, dd, J=8 Hz, J′=1.2 Hz), 6.31 (1H, dd, J=8 Hz, J′=1.2Hz), 6.64 (1H, t, J=7.8 Hz), 9.96 (1H, bs)

Preparation of1-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea

Commercially available 4-trifluoromethylbenzylamine (1 ml, 7 mmol) wasdissolved in 20 ml of AcOEt and at 0° C. triphosgene (2 g, 7 mmol) wasadded to the solution. The mixture was warmed at 80° C. for 4 hours thenevaporated and the residue was dissolved in 5 ml of DMF. The solution ofthe isocyanate was added dropwise to a solution in DMF (10 ml) ofcompound 1e (766 mg, 4.66 mmol) and the mixture was warmed at 80° C. for8 hours. (TLC AcOEt). The solvent was evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 550 mg of a white solid. Yield=32% ¹HNMR (DMSO, 400 MHz) δ 4.40(2H, d, J=5.6 Hz), 4.52 (2H, s), 6.70 (1H, dd, J=8 Hz, J′=1.2 Hz), 6.86(2H, t, J=8 Hz), 7.16 (1H, dd, J=8 Hz, J′=1.2 Hz), 7.54 (2H, d, J=8 Hz),7.70 (2H, d, J=8.4 Hz), 8.18 (1H, s), 10.11 (1H, bs); [M⁺¹] 366.2(C₁₇H₁₄F₃N₃O₃ requires 365.31).

Example 431-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea

Amine 2b (471 mg, 1.94 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (576 mg, 1.94 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1e (213 mg, 1.3mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 120 mg of a white solid.Yield=21% ¹HNMR (DMSO, 400 MHz) δ 1.91 (4H, m), 3.21 (4H, m), 4.48 (2H,d, J=6 Hz), 4.63 (2H, s), 6.64 (2H, dd, J=10.8 Hz, J′=8 Hz), 6.88 (1H,t, J=8 Hz), 7.12 (1H, s), 7.19 (1H, d, J=8.8 Hz), 7.34 (1H, d, J=8 Hz),8.63 (1H, t), 10.68 (1H, bs), 10.90 (1H, bs); [M⁺¹] 435.2 (C₂₁H₂₁F₃N₄O₃requires 434.4).

Example 441-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea

Amine 2c (1 g, 3.8 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt andat 0° C. triphosgene (1.13 g, 3.8 mmol) was added to the solution. Themixture was warmed at 80° C. for 4 hours then evaporated and the residuewas dissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1e (425 mg, 2.6 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column gave 530 mg of a white solid.Yield=45% ¹HNMR (DMSO, 400 MHz) δ 1.56 (2H, bs), 1.69 (4H, bs), 4.55(2H, d, J=5.6 Hz), 4.64 (2H, s), 6.64 (2H, dd, J=14 Hz, J′=7.6 Hz), 6.88(1H, t, J=8 Hz), 7.32 (1H, s), 7.39 (2H, s), 8.64 (1H, t), 10.66 (1H,bs), 10.88 (1H, bs); [M⁺¹] 449.2 (C₂₂H₂₃F₃N₄O₃ requires 448.4).

Example 451-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of 6-chloro-8-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one 12(Scheme 6)

To a solution of 2-amino-4-chloro-6-nitrophenol (5 g, 26.5 mmol) in DMF(20 ml) ethylbromoacetate (3 ml, 26.5 mmol) and K₂CO₃ (4 g, 29.15 mmol)were added and the reaction was stirred at room temperature for 20hours. The solvent was evaporated and the crude was dissolved in AcOEt(30 ml) and washed with NaOH 5%, water and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by crystallization from ether/AcOEtgave 1.13 g of a beige solid. Yield: 19%. ¹HNMR (DMSO, 200 MHz) δ 4.79(2H, s), 7.15 (1H, d, J=2.6 Hz), 7.66 (1H, d, J=2.8 Hz), 11.21 (1H, bs)

Preparation of 8-amino-2H-benzo[b][1,4]oxazin-3(4H)-one 1f

To compound 12 (1.13 g, 4.92 mmol) dissolved in a mixture of 4/1/1MeOH/THF/DMF (60 ml) C/Pd 10% (500 mg) was added and the reaction washydrogenated at 60 psi overnight. (TLC AcOEt 3/petroleum ether 7) Thereaction was filtrated through a pad of Celite and the filtrate wasevaporated under vacuum. The crude solid was crystallized from ethergiving 484 mg of a beige solid. Yield=49%. ¹HNMR (DMSO, 200 MHz) δ 3.80(2H, bs), 4.60 (2H, s), 6.63 (1H, dd, J=7.2 Hz, J′=1.4 Hz), 6.83 (2H,m), 10.79 (1H, bs)

Preparation of1-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Commercially available 4-trifluoromethylbenzylamine (0.6 ml, 4.2 mmol)was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (1.2 g, 4.2mmol) was added to the solution. The mixture was warmed at 80° C. for 4hours then evaporated and the residue was dissolved in 5 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1f (460 mg, 2.8 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crudewas dissolved in AcOEt (30 ml) and washed with water (1×20 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by chromatographiccolumn gave 250 mg of a white solid. Yield=24% ¹HNMR (DMSO, 200 MHz) δ4.31 (2H, d, J=6.2 Hz), 6.46 (1H, dd), 6.70 (2H, t), 6.81 (1H, t), 7.45(2H, d, J=8 Hz), 7.70 (4H, m), 8.16 (1H, s), 10.72 (1H, bs); [M⁺¹] 366.1(C₁₇H₁₄F₃N₃O₃ requires 365.3).

Example 461-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2a (480 mg, 2.2 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (653 mg, 2.2 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1f (320 mg, 1.6mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt1/petroleum ether 1). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 130 mg of a white solid. Yield=19% ¹HNMR (DMSO, 200 MHz) δ 2.70(6H, s), 4.39 (2H, d, J=5.2 Hz), 4.62 (2H, s), 6.48 (1H, dd, J=7.8 Hz,J′=1.2 Hz), 6.81 (1H, t), 7.32 (1H, s), 7.42 (3H, m), 7.72 (1H, dd,J′=1.4 Hz), 8.19 (1H, s), 10.65 (1H, bs); [M⁺¹] 409.1 (C₁₉H₁₉F₃N₄O₃requires 408.37).

Example 471-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2b (750 mg, 3.1 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (920 mg, 3.1 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 5 ml of DMF. The solution of the isocyanate wasadded dropwise to a solution in DMF (10 ml) of compound 1f (620 mg, 3.1mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt1/petroleum ether 1). The solvent was evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 120 mg of a white solid. Yield=9% ¹HNMR (DMSO, 200 MHz) δ 1.89 (4H,m), 3.20 (4H, m), 4.33 (2H, d, J=5.6 Hz), 4.60 (2H, s), 6.45 (1H, dd,J=8 Hz, J′=1.2 Hz), 6.79 (1H, t, J=8.4 Hz), 7.04 (1H, bs), 7.16 (1H, d),7.23 (1H, t), 7.35 (1H, d), 7.72 (1H, dd, J=8.2 Hz, J′=1.4 Hz), 8.16(1H, bs), 10.63 (1H, bs); [M⁺¹] 435.1 (C₂₁H₂₁F₃N₄O₃ requires 434.41).

Example 481-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2c (420 mg, 1.6 mmol) (Scheme 7) was dissolved in 20 ml of AcOEtand at 0° C. triphosgene (475 mg, 1.6 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated anddissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1f (180 mg, 1.1 mmol) andthe mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleumether 1). The solvent was evaporated and the crude was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 160 mgof a white solid. Yield=32% ¹HNMR (DMSO, 200 MHz) δ 1.57 (2H, bs), 1.68(4H, bs), 2.85 (4H, m), 4.39 (2H, d, J=5.6 Hz), 4.62 (2H, s), 6.47 (1H,dd, J=7.8 Hz, J′=1.2 Hz), 6.81 (1H, t, J=8 Hz), 7.31 (2H, m), 7.43 (2H,m), 7.74 (1H, dd, J=8.4 Hz, J′=1.2 Hz), 8.18 (1H, bs), 10.65 (1H, bs);[M⁺¹] 449.2 (C₂₂H₂₃F₃N₄O₃ requires 448.4).

Example 491-(4-chlorobenzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-chlorobenzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Commercially available p-chlorobenzylamine (0.98 ml, 8 mmol) wasdissolved in 40 ml of AcOEt and at 0° C. triphosgene (2.37 g, 1 equiv.)was added to the solution. The mixture was warmed at 80° C. for 4 hoursthen evaporated and the residue was dissolved in 20 ml of DMF. Thesolution of the isocyanate was added dropwise to a solution in DMF (10ml) of compound 1f (1.42 g, 7.11 mmol) and the mixture was warmed at 80°C. for 8 hours. (TLC AcOEt 1/petroleum ether 1). The solvent wasevaporated and to the crude 5% HCl was added. The solid was filtrated,washed with water, MeOH and diethyl ether obtaining 1.6 g of a whiteproduct. Yield=68% ¹HNMR (DMSO, 200 MHz) δ 4.27 (2H, d, J=5.6 Hz), 4.61(2H, s), 6.47 (1H, dd, J=7.8 Hz, J′=1.2 Hz), 6.81 (1H, t, J=8.2 Hz),7.35 (5H, m), 7.73 (1H, dd, J=8.2 Hz, J′=1.2 Hz), 8.10 (1H, bs), 10.65(1H, bs); [M⁺¹] 332.4 (C₁₆H₁₄ClN₃O₃ requires 331.75).

Example 501-(4-chloro-2-(dimethylamino)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-chloro-2-(dimethylamino)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2af (1 g, 5.5 mmol) (Scheme 8) was dissolved in 20 ml of AcOEt andat 0° C. triphosgene (1.63 g, 1 equiv.) was added to the solution. Themixture was warmed at 80° C. for 4 hours then evaporated and the residuewas dissolved in 10 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (10 ml) of compound 1f (860 mg, 4.31 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1 petroleumether 1). The solvent was evaporated and the crude was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 450 mgof a white solid. Yield=28% ¹HNMR (DMSO, 200 MHz) δ 2.63 (6H, m), 4.31(2H, d, J=5.6 Hz), 4.61 (2H, s), 6.47 (1H, dd, J=7.8 Hz, J′=1.6 Hz),6.81 (1H, t, J=8.4 Hz), 7.07 (2H, m), 7.25 (2H, m), 7.75 (1H, dd, J=8.4Hz, J′=1.4 Hz), 8.14 (1H, bs), 10.65 (1H, bs); [M⁺¹] 374.8 (C₁₇H₁₈ClN₄O₃requires 374.82).

Example 511-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2ag (1 g, 4.9 mmol) (Scheme 8) was dissolved in 40 ml of AcOEt andat 0° C. triphosgene (1.46 g, 4.9 mmol) was added to the solution. Themixture was warmed at 80° C. for 4 hours then evaporated and dissolvedin 5 ml of DMF. The solution of the isocyanate was added dropwise to asolution in DMF (20 ml) of compound 1f (980 mg, 4.9 mmol) and themixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleum ether1). The solvent was evaporated and the crude was dissolved in AcOEt (50ml) and washed with water (1×30 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 250 mgof a white solid. Yield=13% ¹HNMR (DMSO, 200 MHz) δ 1.89 (4H, m), 3.17(4H, m), 4.35 (2H, d), 4.61 (2H, s), 6.47 (1H, dd), 6.80 (3H, m), 7.17(2H, m), 7.82 (1H, dd), 8.15 (1H, bs), 10.75 (1H, bs); [M⁺¹] 401.2(C₂₀H₂₁ClN₄O₃ requires 400.86).

Example 521-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2ah (1.7 g, 7.59 mmol) (Scheme 8) was dissolved in 50 ml of AcOEtand at 0° C. triphosgene (2.26 g, 7.59 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated anddissolved in 5 ml of DMF. The solution of the isocyanate was addeddropwise to a solution in DMF (20 ml) of compound 1f (1.5 g, 7.51 mmol)and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleumether 1). The solvent was evaporated and the crude was dissolved inAcOEt (50 ml) and washed with water (1×30 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column gave 210 mgof a white solid. Yield=7% ¹HNMR (DMSO, 200 MHz) δ 1.54 (2H, m), 1.66(4H, m), 2.78 (4H, m), 4.29 (2H, d, J=5.6 Hz), 4.35 (2H, d), 4.61 (2H,s), 6.47 (1H, dd, J=7.8 Hz, J′=1.2 Hz), 6.81 (1H, t, J=8 Hz), 7.13 (4H,m), 7.75 (1H, dd, J=8.2 Hz, J′=1.4 Hz), 8.14 (1H, bs), 10.66 (1H, bs);[M⁺¹] 414.9 (C₂₁H₂₃ClN₄O₃ requires 414.89).

Example 531-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Amine 2bh (1.08 g, 5.3 mmol) (Scheme 8) was dissolved in 40 ml of AcOEtand at 0° C. triphosgene (1.56 g, 5.4 mmol) was added to the solution.The mixture was warmed at 80° C. for 4 hours then evaporated and theresidue was dissolved in 15 ml of DMF. The solution of the isocyanatewas added dropwise to a solution in DMF (10 ml) of compound 1f (1 g,5.46 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt1/petroleum ether 9). The solvent was evaporated and the crude wasdissolved in AcOEt (50 ml) and washed with water (1×30 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columngave 150 mg of a white solid. Yield=7% ¹HNMR (DMSO, 200 MHz) δ 1.63 (6H,m), 2.25 (3H, s), 2.76 (4H, m), 4.28 (2H, d, J=5.4 Hz), 4.61 (2H, s),6.46 (1H, dd, J=7.8 Hz, J′=1.4 Hz), 6.81 (3H, m), 7.12 (2H, m), 7.75(1H, dd, J=8.2 Hz, J′=1.6 Hz), 8.11 (1H, s), 10.66 (1H, bs); [M⁺¹] 395.0(C₂₂H₂₆N₄O₃ requires 394.5).

Example 541-((6-chloropyridin-3-yl)methyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea(scheme 1)

Preparation of1-(((6-chloropyridin-3-yl)methyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea

Commercially available (6-chloropyridin-3-yl)methanamine (800 mg, 5.61mmol) was dissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.54 g,5.6 mmol) was added to the solution. The mixture was warmed at 80° C.for 4 hours then evaporated and the residue was dissolved in 10 ml ofDMF. The solution of the isocyanate was added dropwise to a solution inDMF (10 ml) of compound 1f (900 mg, 4.51 mmol) and the mixture waswarmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent wasevaporated and the crude was dissolved in AcOEt (80 ml) and washed withwater (1×40 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 180 mg of a beige solid.Yield=12% ¹HNMR (DMSO, 200 MHz) δ 4.31 (2H, d, J=5.6 Hz), 4.60 (2H, s),6.47 (1H, dd), 6.81 (1H, t), 7.40 (1H, t), 7.50 (1H, d, J=8.2 Hz), 7.72(2H, m), 8.13 (1H, bs), 8.34 (1H, bs), 10.66 (1H, bs); [M⁺¹] 332.8(C₁₅H₁₃ClN₄O₃ requires 332.74).

Example 552-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)acetamide(scheme 10)

Preparation of2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-4-yl)acetamide

4-trifluoromethylphenylacetic acid (300 mg, 1.47 mmol) was dissolved in20 ml of THF and at 0° C. DEPC (0.28 ml, 1.3 equiv) and amine 1a (260mg, 1.2 equiv.) were added to the solution. The mixture was warmed at80° C. overnight, then evaporated and the crude was dissolved in AcOEt(30 ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column using AcOEtas eluant gave 150 mg of a white solid. Yield=30% ¹HNMR (DMSO, 400 MHz)δ 3.78 (2H, s), 6.75 (1H, d), 6.84 (1H, t), 7.05 (1H, d), 7.56 (2H, d,J=8 Hz), 7.70 (2H, d, J=8 Hz), 9.80 (1H, bs), 10.18 (1H, bs), 10.64 (1H,bs); [M⁺¹] 336.1 (C₁₆H₁₂F₃N₃O₂ requires 335.3).

Example 562-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)acetamide(scheme 10)

Preparation of2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-4-yl)acetamide

4-trifluoromethylphenylacetic acid (453 mg, 2.2 mmol) was dissolved in20 ml of THF and at 0° C. DEPC (0.43 ml, 1.3 equiv) and amine 1b (400mg, 2.66 mmol) were added to the solution. The mixture was warmed at 80°C. overnight, then evaporated and the crude was dissolved in AcOEt (30ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column using AcOEtas eluant gave 360 mg of a white solid. Yield=48% ¹HNMR (DMSO, 200 MHz)δ 3.80 (2H, s), 7.10 (3H, m), 7.58 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.2Hz), 10.06 (1H, bs), 11.14 (1H, bs); [M⁺¹] 336.9 (C₁₆H₁₁F₃N₂O₃ requires336.3).

Example 572-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)acetamide(scheme 10)

Preparation of2-(4-(trifluoromethyl)phenyl)-N-(2,3-dihydro-2-oxobenzo[d]oxazol-7-yl)acetamide

4-trifluoromethylphenylacetic acid (453 mg, 2.2 mmol) was dissolved in20 ml of THF and at 0° C. DEPC (0.43 ml, 1.3 equiv) and amine 1c (400mg, 2.66 mmol) were added to the solution. The mixture was warmed at 80°C. overnight, then evaporated and the crude was dissolved in AcOEt (30ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude residue by chromatographic column using AcOEt3/petroleum ether 7 as eluant gave 340 mg of a white solid. Yield=46%¹HNMR (DMSO, 200 MHz) δ 3.86 (2H, s), 6.86 (1H, d), 7.06 (1H, t), 7.58(3H, m), 7.70 (2H, d, J=8.4 Hz), 10.32 (1H, bs), 8.73 (1H, bs), 11.80(1H, bs); [M⁺¹] 337.2 (C₁₆H₁₁F₃N₂O₃ requires 336.3).

Example 582-(4-(trifluoromethyl)phenyl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)acetamide(scheme 10)

Preparation of2-(4-(trifluoromethyl)phenyl)-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)acetamide

4-trifluoromethylphenylacetic acid (408 mg, 2 mmol) was dissolved in 20ml of THF and at 0° C. DEPC (0.358 ml, 1.2 equiv) and amine 1d (427 mg,2.6 mmol) were added to the solution. The mixture was warmed at 80° C.overnight, then evaporated and the crude was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude residue by chromatographic column using AcOEt as eluant gave550 mg of a white solid. Yield=78.5% ¹HNMR (DMSO, 200 MHz) δ 3.81 (2H,s), 4.55 (2H, s), 6.87 (2H, m), 7.05 (1H, dd, J=7.6 Hz, J′=6 Hz), 7.56(2H, d, J=8.2 Hz), 7.70 (2H, d, J=8 Hz), 9.69 (1H, bs), 10.38 (1H, bs);[M⁺¹] 351.2 (C₁₇H₁₃F₃N₂O₃ requires 350.3).

Example 59N-(4-(trifluoromethyl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide(scheme 11)

Preparation of 2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxylic acid 21

2-amino-3-hydroxybenzoic acid (1.2 g, 7.8 mmol) was suspended in 20 mlof THF and at 0° C. CDI (1.9 g, 1.5 equiv.) was added. The mixture waswarmed at 80° C. for 5 hours. The solvent was evaporated and the crudewas dissolved in AcOEt (30 ml) and washed with water (1×20 ml) andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom EtOAc/ether gave 520 mg of an orange solid. Yield=37% ¹HNMR (DMSO,200 MHz) δ 7.45 (3H, m), 10.40 (1H, bs), 12.00 (1H, bs)

Preparation ofN-(4-(trifluoromethyl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide

2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxylic acid 21 (260 mg, 1.45mmol) was dissolved in 20 ml of THF and at 0° C. DEPC (0.260 ml, 1.2equiv) and 4-chloro-2-trifluorobenzylamine (0.25 ml, 1.2 equiv.) wereadded to the solution. The mixture was warmed at 80° C. overnight, thenevaporated and the crude was dissolved in AcOEt (30 ml) and washed withwater (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column using AcOEt 3/petroleum ether 7 aseluant gave 110 mg of a white solid. Yield=22.5% ¹HNMR (DMSO, 200 MHz) δ4.58 (2H, d, J=5.8 Hz), 7.16 (1H, t, J=8 Hz), 7.42 (1H, dd, J=8.2 Hz,J′=1 Hz), 7.55 (2H, d, J=8.2 Hz), 7.65 (3H, m), 9.29 (1H, bt), 11.60(1H, bs); [M⁺¹] 336.9 (C₁₆H₁₁F₃N₂O₃ requires 336.3).

Example 60N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide(scheme 11)

Preparation ofN-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide

2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxylic acid 21 (560 mg, 3.1 mmol)was dissolved in 20 ml of THF and at 0° C. DEPC (0.55 ml, 1.2 equiv) andamine 2c (964 mg, 1.2 equiv.) were added to the solution. The mixturewas warmed at 80° C. overnight, then evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columnusing AcOEt 4/petroleum ether 6 as eluant gave 250 mg of a pale yellowsolid. Yield=19% ¹HNMR (DMSO, 200 MHz) δ 4.58 (2H, d, J=5.8 Hz), 7.14(1H, t, J=8 Hz), 7.41 (4H, m), 7.68 (1H, dd, J=8 Hz, J′=0.8 Hz), 9.20(1H, bt), 11.59 (1H, bs); [M⁺¹] 420.2 (C₂₁H₂₀F₃N₃O₃ requires 419.4).

Example 61N-(4-(trifluoromethyl)-2-morpholinobenzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide(scheme 11)

Preparation ofN-(4-(trifluoromethyl)-2-morpholinobenzyl)-2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxamide

2,3-dihydro-2-oxobenzo[d]oxazole-4-carboxylic acid 21 (240 mg, 1.3 mmol)was dissolved in 20 ml of THF and at 0° C. DEPC (0.23 ml, 1.2 equiv) andamine 2d (420 mg, 1.2 equiv.) were added to the solution. The mixturewas warmed at 80° C. overnight, then evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columnusing AcOEt 4/petroleum ether 6 as eluant gave 100 mg of a white solid.Yield=18% ¹HNMR (DMSO, 200 MHz) δ 2.94 (4H, bs), 3.78 (4H, bs), 4.64(2H, d, J=5.6 Hz), 7.18 (1H, t), 7.43 (4H, m), 7.66 (1H, d), 9.35 (1H,bs), 11.60 (1H, bs); [M⁺¹] 422.2 (C₂₀H₁₈F₃N₃O₄ requires 421.37).

Example 62N-(4-(trifluoromethyl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-5-carboxamide(scheme 11)

Preparation of N-(4-(trifluoromethyl)benzyl)-2-amino-3-hydroxybenzamide22a

2-amino-3-hydroxybenzoic acid (2 g, 13 mmol) was dissolved in 20 ml ofDMF and at 0° C. EDCI (2.7 g, 1.2 equiv.), hydroxybenzotriazole (1.9 g,1.2 equiv.) and 4-trifluoromethylbenzylamine (2 ml, 1.2 equiv.) wereadded. The mixture was stirred at rt for 20 hours. The solvent wasevaporated and the crude was dissolved in AcOEt (30 ml) and washed withwater (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by crystallization from EtOAc/ether gave 3.5 g of a beige solid.Yield=86% ¹HNMR (DMSO, 200 MHz) δ 4.49 (2H, d, J=5.6 Hz), 6.00 (2H, bs),6.41 (1H, t, J=8 Hz), 6.76 (1H, d, J=7.6 Hz), 7.11 (1H, d, J=8.2 Hz),7.51 (2H, d, J=8 Hz), 7.69 (2H, d, J=8 Hz), 8.81 (1H, bt), 9.58 (1H,bs); [M⁺¹] 311.1 (C₁₅H₁₃F₃N₂O₂ requires 310.27).

Preparation ofN-(4-(trifluoromethyl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-5-carboxamide

N-(4-(trifluoromethyl)benzyl)-2-amino-3-hydroxybenzamide 22a (1 g, 3.2mmol) was dissolved in 20 ml of DMF and at 0° C. TEA (0.9 ml, 2 equiv.)and chloroacetyl chloride (0.3 ml, 1.2 equiv.) were added. The mixturewas stirred at rt for 2 hours. K₂CO₃ (885 mg, 2 equiv.) was added andthe reaction was stirred at rt for 20 hours. The solvent was evaporatedand the crude was dissolved in AcOEt (30 ml) and washed with water (1×20ml) and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bychromatographic column using AcOEt 1/petroleum ether 1 as eluant gave500 mg of a white solid. Yield=44% ¹HNMR (DMSO, 200 MHz) δ 4.56 (2H, d,J=5.4 Hz), 4.65 (2H, s), 7.04 (2H, t), 7.17 (1H, d, J=7.8 Hz), 7.55 (2H,d, J=8 Hz), 7.71 (2H, d, J=8.2 Hz), 9.52 (1H, bs), 10.96 (1H, bs); [M⁺¹]351.1 (C₁₇H₁₃F₃N₂O₃ requires 350.3).

Example 63N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-5-carboxamide(scheme 11)

Preparation ofN-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2-amino-3-hydroxybenzamide22b

2-amino-3-hydroxybenzoic acid (1 g, 6.5 mmol) was dissolved in 20 ml ofDMF and at 0° C. EDCI (1.4 g, 1.2 equiv.), hydroxybenzotriazole (1 g,1.2 equiv.) and amine 2c (2 g, 1.2 equiv.) were added. The mixture wasstirred at rt for 20 hours. The solvent was evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by crystallization fromEtOAc/ether gave 1.6 g of a beige solid. Yield=62.5% [M⁺¹] 393.4(C₂₀H₂₂F₃N₃O₂ requires 393.4).

Preparation ofN-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-5-carboxamide

N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-2-amino-3-hydroxybenzamide22b (2.5 g, 6.4 mmol) was dissolved in 20 ml of DMF and at 0° C. TEA(1.8 ml, 2 equiv.) and chloroacetyl chloride (0.6 ml, 1.2 equiv.) wereadded. The mixture was stirred at rt for 2 hours. K₂CO₃ (1.77 g, 2equiv.) was added and the reaction was stirred at rt for 20 hours. Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column using AcOEt 1/petroleum ether 1as eluant gave 1 g of a white solid. Yield=36% ¹HNMR (DMSO, 200 MHz) δ1.57 (2H, bs), 1.69 (4H, bs), 2.82 (4H, m), 4.60 (2H, d, J=5.4 Hz), 4.67(2H, s), 7.09 (1H, t, J=7.8 Hz), 7.20 (1H, dd, J=8 Hz, J′=1.2 Hz), 7.33(1H, m), 7.41 (2H, m), 7.57 (1H, m), 9.38 (1H, bt), 11.02 (1H, bs);[M⁺¹] 434.3 (C₂₂H₂₂F₃N₃O₃ requires 433.4).

Example 64N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-8-carboxamide(scheme 11)

Preparation ofN-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-amino-2-hydroxybenzamide24b

3-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) was dissolved in 20 ml ofDMF and at 0° C. EDCI (1.4 g, 1.2 equiv.), hydroxybenzotriazole (1 g,1.2 equiv.) and amine 2c (2 g, 1.2 equiv.) were added. The mixture wasstirred at rt for 20 hours. The solvent was evaporated and the crude wasdissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine.The organic phase was dried over sodium sulfate and concentrated undervacuum. The purification of the crude residue by chromatographic columnusing AcOEt 1/petroleum ether 9 as eluant gave 1.3 g of a beige solid.Yield=51% [M⁺¹] 393.4 (C₂₀H₂₂F₃N₃O₂ requires 393.4).

Preparation ofN-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazine-8-carboxamide

N-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-amino-2-hydroxybenzamide24b (830 mg, 2.1 mmol) was dissolved in 10 ml of DMF and at 0° C. TEA(0.58 ml, 2 equiv.) and chloroacetyl chloride (0.2 ml, 1.2 equiv.) wereadded. The mixture was stirred at rt for 2 hours. K₂CO₃ (580 mg, 2equiv.) was added and the reaction was stirred at rt for 20 hours. Thesolvent was evaporated and the crude was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by chromatographic column using AcOEt 1/petroleum ether 1as eluant gave 460 mg of a white solid. Yield=50% ¹HNMR (DMSO, 200 MHz)δ 1.57 (2H, bs), 1.69 (4H, bs), 2.84 (4H, m), 4.58 (2H, d, J=5.2 Hz),4.69 (2H, s), 7.03 (2H, m), 7.30 (2H, m), 7.45 (2H, m), 8.70 (1H, bt),10.85 (1H, bs); [M⁺¹] 434.1 (C₂₂H₂₂F₃N₃O₃ requires 433.4).

Example 65 3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl4-(trifluoromethyl)benzylcarbamate (scheme 12)

Preparation of 5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one 25

TEA (3.34 ml, 2 equiv.) and after chloroacetyl chloride (1.15 ml, 1.2equiv.) were added dropwise to a solution of commercially available2-aminobenzene-1,3-diol (1.5 g, 11.99 mmol) in 20 ml of DMF. After onehours of stirring at room temperature, K₂CO₃ (3.3 g, 2 equiv.) was addedand the reaction was stirred at room temperature overnight. The solventwas evaporated and to the residue water was added. After filtration, thesolid material was washed with MeOH and diethyl ether giving 410 mg of agrey solid. Yield=21% ¹HNMR (DMSO, 200 MHz) δ 3.47 (1H, bs), 4.47 (2H,s), 6.44 (2H, m), 6.72 (1H, t, J=8 Hz)

Preparation of 3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl4-(trifluoromethyl)benzylcarbamate

4-trifluoromethylbenzylamine (0.52 ml, 3.6 mmol) was dissolved in 20 mlof AcOEt and at 0° C. triphosgene (1 g, 3.6 mmol) was added to thesolution. The mixture was warmed at 80° C. for 4 hours then evaporatedand the residue was dissolved in 5 ml of DMF. The solution of theisocyanate was added dropwise to a solution in DMF (10 ml) of compound25 (400 mg, 2.42 mmol) and TEA (0.34 ml, 1 equiv.) and the mixture wasstirred at rt for 8 hours. (TLC AcOEt 1/petroleum ether 1). The solventwas evaporated and the crude was dissolved in AcOEt (30 ml) and washedwith water (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by chromatographic column gave 400 mg of a white solid.Yield=45% ¹HNMR (DMSO, 200 MHz) δ 4.38 (2H, d, J=6.4 Hz), 4.57 (2H, s),6.85 (3H, m), 7.59 (2H, d, J=8.2 Hz), 7.72 (2H, d, J=8.4 Hz), 8.15 (1H,bt), 10.61 (1H, bs); [M⁺¹] 367.1 (C₁₇H₁₃F₃N₂O₄ requires 366.3).

Example 661-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea

Preparation of1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea

To a solution of 3-aminomethyl-6-trifluoromethylpyridine (1 g, 4.7 mmol)in THF (30 mL) was added CDI (2.1 mol eq) and the mixture was heated at70° C. overnight. The reaction mixture was evaporated, water was addedand the aqueous phase was extracted with EtOAc (3×20 mL). The recombinedorganic phases were anhydrified over Na₂SO₄ and evaporated at reducedpressure. The oil obtained (0.96 g, 3.5 mmol) was dissolved in DMF (20mL) and the bicyclic amine 1a was added (0.8 mol eq), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by crystallization from amixture of MeOH/EtOAc to obtain the product as a pale yellow solid (0.42g, 1.2 mmol, 34% Yield). ¹HNMR (DMSO, 400 MHz) δ 4.43 (bs, 2H), 6.64 (d,1H, J=6), 6.83 (t, 1H, J=8), 6.96 (d, 2H, J=8), 7.89 (d, 1H), 8.03 (d,1H), 8.42 (bs, 1H), 8.72 (s, 1H), 10.07 (bs, 1H), 10.59 (bs, 1H). [M⁺¹]351.80 (C₁₅H₁₂F₃N₅O₂ requires 351.28).

Example 671-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of 2-isopropoxy-4-(trifluoromethyl)benzonitrile 26a (Scheme13)

The 2-fluoro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.59 mmol) wasadded in small portion to a mixture of NaH 60% (4 mol eq) in isopropanol(10 mL). The reaction mixture was heated at 50° C. overnight. Thesolvent was distilled and water was added to the residue. The aqueoussolution was extracted with EtOAc (3×25 mL) and the organic phases wereevaporated at reduced pressure to give e as a white solid (0.84 g,quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.23 (s, 3H), 1.34 (s, 3H),4.99 (m, 1H), 7.44 (m, 2H), 8.01 (d, 1H, J=8).

Preparation of [2-isopropoxy-4-(trifluoromethyl)phenyl]methanamine 27a

The nitrile 26a (0.84 g, 3.66 mmol)) was added in small portion to amixture of LiAlH₄ (0.28 g, 2 mol eq) in Et₂O (30 mL) stirred at 0° C.Then the mixture was stirred at room temperature overnight. The excessof LiAlH₄ was decomposed by water addition at 0° C., the solid formedwas filtered, washed with Et₂O and the filtrate was separated. Theorganic phase was anhydrified over Na₂SO₄ and evaporated to dryness toobtain 27a as yellow oil (0.80 g, 3.64 mmol, 96% Yield).

Preparation of1-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 27a (0.85 g, 3.6 mmol) in THF (30 mL) was added CDI(2.1 mol eq, 1.24 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale yellowoil, 1.25 g, quantitative yield). The oil obtained (0.59 g) wasdissolved in DMF (20 mL) and the bicyclic amine 1a was added (0.8 moleq, 0.21 g), then the mixture obtained was heated at 100° C. overnight.The solvent was removed at reduced pressure and the residue was purifiedby chromatography (100% EtOAc) to obtain the product as a white crystalsolid (0.15 g, 0.4 mmol, 36% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.29 (s,3H), 1.32 (s, 3H), 4.32 (d, 2H, J=6), 4.79 (m, 1H), 6.60 (m, 2H),6.79-6.96 (m, 2H), 7.28 (d, 2H), 7.46 (d, 1H, J=6), 8.37 (s, 1H), 10.0(bs, 1H), 10.60 (bs, 1H). [M⁺¹] 409.1 (C₁₉H₁₉F₃N₄O₃ requires 408.37).

Example 681-[[2-isopropoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of 2-isopropoxy-6-(trifluoromethyl)pyridine-3-carbonitrile28a (Scheme 14)

The 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) wasadded in small portion to a mixture of NaH 60% (4 mol eq) in isopropanol(20 mL). The reaction mixture was heated at 50° C. overnight. Thesolvent was distilled and water was added to the residue. The aqueoussolution was extracted with EtOAc (3×25 mL) and the organic phases wereevaporated at reduced pressure to give e as a yellow solid (0.45 g, 82%Yield, 1.96 mmol). ¹HNMR (DMSO, 200 MHz) δ 1.35 (s, 3H), 1.38 (s, 3H),5.33 (m, 1H), 7.55 (d, 1H, J=6), 8.26 (d, 1H, J=6).

Preparation of [2-isopropoxy-6-(trifluoromethyl)-3-pyridyl]methanamine29a

The nitrile 28a (0.45 g, 1.96 mmol)) was added in small portion to amixture of LiAlH₄ (0.15 g, 2 mol eq) in Et₂O (30 mL) stirred at 0° C.Then the mixture was stirred at room temperature overnight. The excessof LiAlH₄ was decomposed by water addition at 0° C., the solid formedwas filtered, washed with Et₂O and the filtrate was separated. Theorganic phase was anhydrified over Na₂SO₄ and evaporated to dryness toobtain 29a as yellow oil (0.42 g, 1.79 mmol, 94% Yield) used for thenext reaction without further purification.

Preparation of1-[[2-isopropoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 29a (0.42 g, 1.8 mmol) in THF (25 mL) was added CDI(2.1 mol eq, 0.61 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale yellowoil, 0.52 g, quantitative yield). The oil obtained (0.25 g) wasdissolved in DMF (15 mL) and the bicyclic amine 1a was added (0.8 moleq, 0.09 g), then the mixture obtained was heated at 100° C. overnight.The solvent was removed at reduced pressure and the residue was purifiedby chromatography (100% EtOAc) to obtain the product as a pale yellowsolid (0.08 g, 0.4 mmol, 27% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.33 (s,3H), 1.36 (s, 3H), 4.28 (d, 2H, J=6), 5.28 (m, 1H), 6.64 (m, 2H),6.87-6.93 (m, 2H), 7.46 (d, 1H, J=8), 7.78 (d, 1H), 8.41 (s, 1H), 9.99(bs, 1H), 10.62 (bs, 1H). [M⁺¹] 409.7 (C₁₈H₁₈F₃N₅O₃ requires 409.36).

Example 691-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of2-dimethylamino-6-(trifluoromethyl)pyridine-3-carbonitrile 28d (Scheme14)

To 2-chloro-6-(trifluoromethyl)nicotinonitrile (0.8 g, 3.8 mmol) wasadded hexamethylphosphoramide (6 mol eq, 4.16 mL) and the mixture washeated at 150° C. for 48 h. The reaction mixture was cooled at roomtemperature, water and brine were added and the mixture was extractedwith EtOAc (4×35 mL). The recombined organic phases were dried oversodium sulfate and evaporated to dryness to obtain 28d as yellow oil(1.01 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.33 (s, 3H), 1.38(s, 3H), 7.41 (d, 1H, J=6), 7.55 (d, 1H, J=6).

Preparation of3-(aminomethyl)-N,N-dimethyl-6-(trifluoromethyl)pyridin-2-amine 29d

The nitrile 28d (1 g, 4.6 mmol)) was added in small portion to a mixtureof LiAlH₄ (0.5 g, 2 mol eq) in Et₂O (30 mL) stirred at 0° C. Then themixture was stirred at room temperature overnight. The excess of LiAlH₄was decomposed by water addition at 0° C., the solid formed wasfiltered, washed with Et₂O and the filtrate was separated. The organicphase was anhydrified over Na₂SO₄ and evaporated to dryness to obtain29d as yellow oil (0.78 g, 3.5 mmol, 76% Yield) used without furtherpurifications.

Preparation of1-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 29d (0.78 g, 3.5 mmol) in THF (35 mL) was added CDI(2.1 mol eq, 1.21 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×25 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale orangeoil, quantitative yield). The oil obtained (0.7 g, 2.4 mmol) wasdissolved in DMF (30 mL) and the bicyclic amine 1a was added (0.8 moleq, 0.26 g), then the mixture obtained was heated at 100° C. overnight.The solvent was removed at reduced pressure and the residue was purifiedby chromatography (9.5:0.5 EtOAc:MeOH) to obtain the product as a paleyellow solid (0.08 g, 0.2 mmol, 20% Yield). ¹HNMR (DMSO, 400 MHz) δ 2.84(s, 6H), 4.38 (d, 2H, J=6), 6.60 (dd, 1H), 6.79 (m, 2H), 6.99 (m, 1H),7.37 (d, 1H, J=6), 7.84 (d, 1H, J=8), 8.37 (s, 1H), 10.0 (bs, 1H), 10.60(bs, 1H). [M⁺¹] 394.9 (C₁₇H₁₇F₃N₆O₂ requires 394.35).

Example 701-[(4-tert-butylphenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 4-tert-butylbenzylamine (2 mL, 11.36 mmol) in THF (30mL) was added CDI (2.1 mol eq, 3.86 g) and the mixture was heated at 70°C. overnight. The reaction mixture was evaporated, water was added andthe aqueous phase was extracted with EtOAc (3×30 mL). The recombinedorganic phases were anhydrified over Na₂SO₄ and evaporated at reducedpressure (pale yellow oil, quantitative yield). The oil obtained (1.6 g,6.2 mmol)) was dissolved in DMF (25 mL) and the bicyclic amine 1a wasadded (0.8 mol eq, 0.74 g), then the mixture obtained was heated at 100°C. overnight. The solvent was removed at reduced pressure and theresidue was purified by crystallization from MeOH to obtain the productas a white solid (0.54 g, 1.59 mmol, 26% Yield). ¹HNMR (DMSO, 400 MHz) δ1.26 (s, 9H), 4.28 (d, 2H, J=6), 6.34 (dd, 1H), 6.36 (t, 1H), 6.83-6.91(m, 2H), 7.26 (d, 2H, J=8), 7.37 (d, 2H, J=8), 8.20 (s, 1H 9, 9.89 (bs,1H), 10.61 (bs, 1H). [M⁺¹] 338.82 (C₁₉H₂₂N₄O₂ requires 338.40).

Example 711-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-(1-piperidyl)-6-(trifluoromethyl)-3-pyridyl]methyl]urea

Preparation of2-(1-piperidyl)-6-(trifluoromethyl)-pyridine-3-carbonitrile 28f (Scheme14)

To 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.42 mmol) in EtOHabs (20 mL) was added piperidine (4 mol eq, 1 mL) and the mixture washeated at 90° C. for 3 h. The mixture was concentrated, water was addedand the mixture was extracted with EtOAc (3×20 mL). The recombinedorganic phases were anhydrified and evaporated to dryness to obtain2-(1-piperidyl)-6-trifluoromethyl)-pyridine-3-carbonitrile as paleyellow oil (0.67 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 3.33(m, 4H), 3.56 (m, 4H), 7.25 (d, 1H), 7.36 (d, 1H, J=6).

Preparation of2-(1-piperidyl)-6-(trifluoromethyl)-3-aminomethyl-pyridine 29f

The nitrile 28f (0.67 g, 2.66 mmol) solubilized in Et₂O (20 mL) wasadded in small portion to a mixture of LiAlH₄ (0.202 g, 2 mol eq) inEt₂O (25 mL) stirred at 0° C. Then the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was decomposed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was separated. The organic phase was anhydrified overNa₂SO₄ and evaporated to dryness to obtain 29f as yellow oil (0.48 g,1.85 mmol, 69% Yield) used without further purifications.

Preparation of1-(2-oxo-1,3-dihydrobenzimidazol-4-yl)-3-[[2-piperidyl-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea

To a solution of 29f (0.48 g, 1.85 mmol) in THF (20 mL) was added CDI(2.1 mol eq, 0.63 g) and the mixture was heated for 5 h. The reactionmixture was evaporated, water was added and the aqueous phase wasextracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure. The oilobtained (0.78 g, quantitative yield) was dissolved in DMF (20 mL) andthe bicyclic amine 1a was added (0.8 mol eq, 0.26 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by chromatography (9.5:0.5EtoAc:MeOH) to obtain the product as a pale yellow solid (0.14 g, 0.32mmol, 15% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.63 (m, 6H), 3.09 (m, 4H),4.36 (d, 2H, J=6), 6.61 (d, 1H, J=8), 6.84 (t, 2H), 6.95 (d, 1H, J=6),7.42 (d, 1H, J=8), 7.87 (d, 1H, J=6), 8.37 (s, 1H), 10.01 (bs, 1H),10.59 (bs, 1H). [M⁺¹] 434.91 (C₂₀H₂₁F₃N₆O₂ requires 434.41).

Example 721-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)pyridine-3-carbonitrile 28b(Scheme 14)

To N,N-dimethylaminoethanol (25 mL) at 0° C. was added in small portionNaH 60% (4 mol eq, 0.465 g, 11.62 mmol) and after 10 min2-chloro-6-trifluoromethyl-nicotinonitrile (0.6 g, 2.90 mmol) was slowlyadded. The mixture was heated at 65° C. for 4 h. Then the solvent wasremoved at reduced pressure, water was added and the aqueous phase wasextracted with EtOAc (3×30 mL). The recombined organic phases werewashed with brine, anhydrified over Na₂SO₄ and evaporated at reducedpressure to obtain a pale yellow oil (0.69 g, 2.66 mmol, 92% Yield) usedfor the next step of reaction without further purification.

Preparation of2-[[3-(aminomethyl)-6-(trifluoromethyl)-2-pyridyl]oxy]-N,N-dimethyl-ethanamine29b

The nitrile 28b (2.66 mmol) was dissolved in EtOH abs (30 mL), C/Pd 10%(0.25 mg) was added and the mixture was hydrogenated at 70 psiovernight. The reaction mixture was filtered through a celite pad andthe filtrate was evaporated at reduced pressure to give 29b as brown oil(0.6 g, 2.28 mmol, 86% Yield) ¹HNMR (DMSO, 200 MHz) δ 2.20 (s, 6H), 2.65(t, 2H), 3.23 (m, 2H), 4.01 (m, 2H), 7.60 (d, 1H), 7.99 (bs, 2H), 8.38(d, 1H, J=8).

Preparation of1-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 29b (0.6 g, 2.28 mmol) in THF (20 mL) was added CDI(2.1 mol eq, 0.78 g) and the mixture was heated at 70° C. for 6 h. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×25 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (yellow oil,0.72 g, 88% yield). The oil obtained was dissolved in DMF (20 mL) andthe bicyclic amine 1a was added (0.8 mol eq, 0.24 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by chromatography (8:2EtOAc:MeOH) to obtain the product as a pale yellow solid (0.088 g, 0.158mmol, 10% Yield). ¹HNMR (DMSO, 400 MHz) δ 2.27 (s, 6H), 2.73 (t, 2H),4.25 (d, 2H, J=6), 4.46 (t, 2H), 6.60 (d, 1H), 6.83 (m, 2H), 7.01 (d,1H), 7.43 (d, 1H), 7.80 (d, 1H), 8.60 (s, 1H), 10.02 (bs, 1H), 10.62(bs, 1H). [M⁺¹] 439.02 (C₁₉H₂₁F₃N₆O₃ requires 438.40).

Example 731-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea(Scheme 13)

Preparation of 2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)benzonitrile26b

To N,N-dimethylaminoethanol (15 mL) cooled at 0° C. was added NaH 60%(1.15 g, 4 mol eq) and then 2-fluoro-4-trifluoromethyl-benzonitrile (1mL, 7.18 mmol). The mixture was heated at 60° C. for 4 h then thesolvent was removed at reduced pressure and water was added to theresidue. The aqueous phase was extracted with EtOAc (3×30 mL), theorganic phases were dried over sodium sulfate and evaporated to drynessto give 26b as pale yellow oil (2.1 g, quantitative yield). ¹HNMR (DMSO,200 MHz) δ 1.21 (s, 3H), 1.31 (s, 3H), 2.21 (t, 2H, J=8), 2.48 (t, 2H,J=8), 6.54 (dd, 1H, J=2), 6.82 (m, 2H).

Preparation of2-[2-(aminomethyl)-5-(trifluoromethyl)phenoxy]-N,N-dimethyl-ethanamine27b

The nitrile 26b (2.15 g, 8.33 mmol) solubilized in Et₂O (20 mL) wasadded in small portion to a mixture of LiAlH₄ (0.63 g, 2 mol eq) in Et₂O(25 mL) stirred at 0° C. Then the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was decomposed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was separated. The organic phase was anhydrified overNa₂SO₄ and evaporated to dryness to obtain 27b as yellow oil (1.48 g,5.64 mmol, 67% Yield) used without further purifications.

Preparation of1-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 27b (1.48 g, 5.64 mmol) in THF (25 mL) was added CDI(2.1 mol eq, 1.92 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×30 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale yellowoil, 1.91 g, 95% yield). The oil obtained (0.95 g, 2.68 mmol) wasdissolved in DMF (20 mL) and the bicyclic amine 1a was added (0.8 moleq, 0.32 g), then the mixture obtained was heated at 100° C. overnight.The solvent was removed at reduced pressure and the residue was purifiedby chromatography (8:2 EtOAc:MeOH) to obtain the product as a whitesolid (0.17 g, 20% Yield). ¹HNMR (DMSO, 400 MHz) δ 2.24 (s, 6H), 2.68(t, 2H, J=6), 4.19 (t, 2H, J=6), 4.32 (d, 2H, J=6), 6.60 (m, 2H), 6.67(t, 1H), 6.93 (d, 1H, J=4), 7.28 (m, 2H), 7.43 (d, 1H), 8.40 (s, 1H),9.98 (s, 1H), 10.60 (s, 1H). [M⁺¹] 438.01 (C₂₀H₂₂F₃N₅O₃ requires437.42).

Example 741-[(4-tert-butyl-2-chloro-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of 4-tert-butyl-2-chloro-benzonitrile 9 (Multi-stepsreaction) (Scheme 4)

-   -   To a solution of 4-tert-butylacetanilide 7 (5 g, 26.1 mmol) in        DMF (30 mL) was added at 0° C. NCS (1.5 mol eq, 5.23 g) and the        mixture was stirred at room temperature overnight. Water was        added and the solid formed was filtered off to furnish 8 as pale        yellow solid (quantitative yield, 5.8 g).    -   The acetyl 8 was deprotected by treatment with aqueous HCl 20%        overnight to furnish the aniline derivative as red oil (75%        Yield).    -   The aniline derivative of 8 (5 g, 5.43 mmol) was solubilized in        10:6 HOAc:water (35 mL). To this solution was added conc. H₂SO₄        (4.5 mL) and this solution was cooled at 10° C. and treated with        a solution of NaNO₂ (2.1 g, 1.1 mol eq) in water (5 mL). After        this addition was completed the reaction mixture was stirred at        10° C. for 1 h. During this time a solution of        tetra-butylammonium cyanide (36.4 g, 5 mol eq) in water (25 mL)        was added to a cold stirred solution of CuSO₄x5H₂O (8.2 g, 1.2        mol eq) in water (25 mL). To this mixture was added NaHCO₃        (18.15 g) and toluene (50 mL) and the resulting mixture was        heated at 55° C. to dissolve the solid formed. To this solution        was added drop wise the solution of the diazonium salt under N₂        at 55° C. The reaction mixture was kept for 30 min. at 55° C.        and then was cooled and extracted three times with toluene. The        combined organic extracts were washed with 1N NaOH and brine,        then dried and evaporated to dryness to obtain a red-brown oil        purified by chromatography (9.5:0.5 petroleum ether:EtOAc) to        furnish the nitrile 9 as a red oil (2.2 g, 43% Yield). ¹HNMR        (DMSO, 200 MHz) δ 1.28 (s, 9H), 7.54 (dd, 1H, J=2), 7.71 (d, 1H,        J=2), 7.96 (d, 1H, J=8).

Preparation of (4-tert-butyl-2-chloro-phenyl)-methanamine 11c

The nitrile 9 (0.97 g, 4 mmol) solubilized in Et₂O (30 mL) was added insmall portion to a mixture of LiAlH₄ (0.3 g, 2 mol eq) in Et₂O (25 mL)stirred at 0° C. Then the mixture was stirred at room temperatureovernight. The excess of LiAlH₄ was decomposed by water addition at 0°C., the solid formed was filtered, washed with Et₂O and the filtrate wasseparated. The organic phase was anhydrified over Na₂SO₄ and evaporatedto dryness to obtain 11c as orange oil (1 g, quantitative Yield), usedfor the next step of reaction without further purification.

Preparation of1-[(4-tert-butyl-2-chloro-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 11c (1 g, 4.6 mmol) in THF (40 mL) was added CDI (2.1mol eq, 1.4 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×30 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (red oil,1.36 g, 98% yield). The oil obtained (1.36 g, 3.99 mmol) was dissolvedin DMF (20 mL) and the bicyclic amine 1a was added (0.8 mol eq, 0.47 g),then the mixture obtained was heated at 100° C. overnight. The solventwas removed at reduced pressure and the residue was purified bychromatography (100% EtOAc) to obtain the product as a white solid (0.29g, 21% Yield). ¹HNMR (DMSO, 200 MHz) δ 1.26 (s, 9H), 4.35 (d, 2H, J=6),6.64 (d, 1H, J=8), 6.87 (m, 3H), 7.40 (m, 3H), 8.31 (s, 1H), 9.94 (bs,1H), 10.59 (bs, 1H). [M⁺¹] 373.05 (C₁₉H₂₁ClN₄O₂ requires 372.85).

Example 751-[(4-tert-butyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

Preparation of 4-tert-butyl-2-pyrrolidin-1-yl-benzonitrile 10a(Multi-steps reaction) (Scheme 4)

The nitrile 9 (2.2 g, 11.3 mmol) was heated in a steel-bomb withpyrrolidine (3.75 mL, 4 mol eq) at 200° C. for 12 h. The reactionmixture was concentrated, water and brine was added and the mixture wasextracted three times with EtOAc. The recombined organic phases weredried under sodium sulfate and evaporated to dryness to furnish 10a as ared oil (2.6 g, quantitative yield), used for the next step of reactionwithout further purifications.

Preparation of (4-tert-butyl-2-pyrrolidin-1-yl-phenyl)methanamine 11a

The nitrile 10a (2.6 g, 11.4 mmol) solubilized in Et₂O (30 mL) was addedin small portion to a mixture of LiAlH₄ (0.87 g, 2 mol eq) in Et₂O (25mL) stirred at 0° C. Then the mixture was stirred at room temperatureovernight. The excess of LiAlH₄ was decomposed by water addition at 0°C., the solid formed was filtered, washed with Et₂O and the filtrate wasseparated. The organic phase was anhydrified over Na₂SO₄ and evaporatedto dryness to obtain 11a as orange oil (2.7 g, quantitative Yield).¹HNMR (DMSO, 200 MHz) δ 1.25 (s, 9H), 1.82 (m, 4H), 2.49 (m, 4H), 3.09(m, 2H), 3.67 (m, 2H), 6.86 (dd, 1H), 7.35 (m, 2H).

Preparation of1-[(4-tert-butyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(2-oxo-1,3-dihydrobenzimidazol-4-yl)urea

To a solution of 11a (2.7 g, 11.6 mmol) in THF (40 mL) was added CDI(2.1 mol eq, 3.96 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×30 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (red oil, 3.6g, 95% yield). The oil obtained (1.8 g, 5.52 mmol) was dissolved in DMF(20 mL) and the bicyclic amine 1a was added (0.8 mol eq, 0.65 g), thenthe mixture obtained was heated at 100° C. overnight. The solvent wasremoved at reduced pressure and the residue was purified bychromatography (100% EtOAc) to obtain the product as a white solid (0.17g, 20% Yield). ¹HNMR (DMSO, 200 MHz) δ 1.26 (s, 9H), 1.88 (m, 4H), 3.13(m, 4H), 4.31 (d, 2H, J=6), 6.52 (bt, 1H), 6.59 (d, 1H, J=8), 6.93 (m,4H), 7.19 (d, 1H, J=8), 8.26 (s, 1H), 9.93 (bs, 1H), 10.59 (bs, 1H).[M⁺¹] 408.03 (C₂₃H₂₉N₅O₂ requires 407.51).

Example 761-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea

Preparation of1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea

To a solution of [5-(trifluoromethyl)-2-furyl]methanamine (0.48 g, 2.91mmol) in THF (20 mL) was added CDI (2.1 mol eq, 0.99 g) and the mixturewas heated at 70° C. overnight. The reaction mixture was evaporated,water was added and the aqueous phase was extracted with EtOAc (3×25mL). The recombined organic phases were anhydrified over Na₂SO₄ andevaporated at reduced pressure (yellow oil, 1.68 g, quantitative yield).The oil obtained was dissolved in DMF (20 mL) and the bicyclic amine 1fwas added (0.8 mol eq, 0.57 g), then the mixture obtained was heated at100° C. overnight. The solvent was removed at reduced pressure and theresidue was purified by crystallization from a mixture of MeOH/EtOAc toafford the product as a pale yellow solid (0.088 g, 10% Yield). ¹HNMR(DMSO, 400 MHz) δ 4.37 (d, 2H, J=6), 4.60 (s, 2H), 6.46 (m, 2H), 6.77(t, 1H, J=8), 7.16 (m, 1H), 7.37 (t, 1H), 7.72 (dd, 1H, J=2), 8.16 (s,1H), 10.64 (bs, 1H).

Example 771-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea

To a solution of 3-aminomethyl-6-trifluoromethylpyridine (1 g, 4.7 mmol)in THF (30 mL) was added CDI (2.1 mol eq) and the mixture was heated at70° C. overnight. The reaction mixture was evaporated, water was addedand the aqueous phase was extracted with EtOAc (3×20 mL). The recombinedorganic phases were anhydrified over Na₂SO₄ and evaporated at reducedpressure. The oil obtained (0.8 g, 2.96 mmol) was dissolved in DMF (20mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.47 g), then themixture obtained was heated at 100° C. overnight. The solvent wasremoved at reduced pressure and the residue was purified bychromatography (100% EtOAc) to obtain the product as a pale yellow solid(0.37 g, 42% Yield). ¹HNMR (DMSO, 200 MHz) δ 4.39 (d, 2H, J=6), 4.61 (s,2H), 6.46 (dd, 1H, J=2), 6.81 (t, 1H, J=8), 7.43 (t, 1H), 7.68 (dd, 1H,J=2), 7.90 (m, 2H), 8.18 (s, 1H), 8.69 (s, 1H), 10.66 (s, 1H). [M⁺¹]355.88 (C₁₅H₁₃F₃N₃O₃ requires 355.27).

Example 781-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[2-(1-piperidyl)-6-(trifluoromethyl)-3-pyridyl]methyl]urea(Scheme 14)

To a solution of 29f (0.48 g, 1.85 mmol) in THF (20 mL) was added CDI(2.1 mol eq, 0.63 g) and the mixture was heated for 5 h. The reactionmixture was evaporated, water was added and the aqueous phase wasextracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure. The oilobtained (0.78 g, quantitative yield) was dissolved in DMF (20 mL) andthe bicyclic amine 1f was added (0.8 mol eq, 0.23 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by chromatography (1:1EtoAc:petroleum ether) to obtain the product as a pale yellow solid(0.067 g, 13% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.62 (m, 6H), 3.09 (m,4H), 4.33 (d, 2H, J=6), 4.62 (s, 2H), 6.46 (dd, 1H, J=2), 6.81 (t, 1H,J=8), 7.42 (bt, 1H), 4.46 (d, 1H, J=8), 7.74 (m, 2H), 8.20 (s, 1H),10.66 (s, 1H). [M⁺¹] 450.02 (C₂₁H₂₂F₃N₅O₃ requires 449.43).

Example 79 1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-(p-tolylmethyl)urea

To a solution of 4-methylbenzylamine (1.5 mL, 11.8 mmol) in THF (30 mL)was added CDI (2.1 mol eq, 3.8 g) and the mixture was heated at 70° C.overnight. The reaction mixture was evaporated, water was added and theaqueous phase was extracted with EtOAc (3×30 mL). The recombined organicphases were anhydrified over Na₂SO₄ and evaporated at reduced pressureto give a white solid (11.78 mmol, 2.53 g, quantitative yield). Thesolid obtained (0.83 g, 3.88 mmol) was dissolved in DMF (20 mL) and thebicyclic amine 1f was added (0.8 mol eq, 0.62 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by crystallization fromhot MeOH to give the product as pale yellow solid (0.078 g, 8% Yield).¹HNMR (DMSO, 200 MHz) δ 2.27 (s, 3H), 4.24 (d, 2H, J=6), 4.59 (s, 2H),6.28 (t, 1H), 4.47 (dd, 1H), 6.80 (t, 1H, J=8), 7.11-7.21 (m, 4H), 7.77(dd, 1H, J=2), 8.07 (s, 1H), 10.63 (bs, 1H). [M⁺¹] 311.99 (C₁₇H₁₇N₃O₃requires 311.34).

Example 801-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 16)

To a solution of 33b (1.06 g, 5.18 mmol) in THF (20 mL) was added CDI(2.1 mol eq, 1.76 g) and the mixture was heated for 6 h. The reactionmixture was evaporated, water was added and the aqueous phase wasextracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure to give anoil (1.04 g, 3.36 mmol). One portion (0.5 g, 1.67 mmol) was dissolved inDMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.25 g),then the mixture obtained was heated at 100° C. overnight. The solventwas removed at reduced pressure and the residue was purified bychromatography (1:1 EtOAc:petroleum ether) to obtain the product as awhite solid (0.13 g, 28% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.63 (m, 6H),2.48 (s, 3H), 2.94 (m, 4H), 4.24 (d, 2H, J=6), 4.61 (s, 2H), 6.45 (dd,1H, J=2), 6.83 (m, 2H), 7.21 (bt, 1H), 7.48 (d, 1H, J=8), 7.76 (dd, 1H,J=2), 8.12 (s, 1H), 10.65 (s, 1H). [M⁺¹] 396.03 (C₂₁H₂₅N₅O₃ requires395.45).

Example 811-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 13)

To a solution of 27a (0.85 g, 3.6 mmol) in THF (30 mL) was added CDI(2.1 mol eq, 1.24 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×20 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale yellowoil, 1.25 g, quantitative yield). The oil obtained (0.6 g, 1.82 mmol)was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8mol eq, 0.29 g), then the mixture obtained was heated at 100° C.overnight. The solvent was removed at reduced pressure and the residuewas purified by chromatography (1:1 EtOAc:petroleum ether) to obtain theproduct as a white solid (0.121 g, 0.29 mmol, 16% Yield). ¹HNMR (DMSO,400 MHz) δ 1.29 (s, 3H), 1.32 (s, 3H), 4.28 (d, 2H, J=6), 4.62 (s, 2H),4.79 (m, 1H), 6.49 (dd, 1H, J=2), 6.80 (t, 1H, J=8), 7.25 (m, 4H), 7.71(dd, 1H), 8.21 (s, 1H), 10.65 (s, 1H). [M⁺¹] 423.97 (C₂₀H₂₀F₃N₃O₄requires 423.38).

Example 821-[[2-methoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 14)

Preparation of 2-methoxy-6-(trifluoromethyl)pyridine-3-carbonitrile 28c

To 2-chloro-6-trifluoromethyl-nicotinonitrile (0.5 g, 2.4 mmol) inmethanol (30 mL) was added sodium methylate in small portion (2 mol eq,0.26 g). The reaction mixture was heated at 60° C. overnight. Thesolvent was distilled under reduced pressure and water was added to theresidue. The aqueous solution was extracted with EtOAc (3×25 mL) and theorganic phases were evaporated at reduced pressure to give 28c as a paleyellow oil (0.48 g, 2.33 mmol, 97% Yield). ¹HNMR (DMSO, 200 MHz) δ 4.04(s, 3H), 7.71 (d, 1H, J=6), 8.59 (d, 1H, J=6).

Preparation of [2-methoxy-6-(trifluoromethyl)-3-pyridyl]methanamine 29c

The nitrile 28c (0.48 g, 2.33 mmol) was solubilized in MeOH (30 mL) andto the solution was added Pd/C 10% (0.3 g). The mixture was hydrogenatedat 70 psi overnight. The reaction mixture was filtered through a celitepad, the filtrate was evaporated at reduce pressure to furnish 29c asyellow oil (0.38 g, 1.84 mmol, 79% Yield) used without furtherpurification.

Preparation of1-[[2-methoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

To a solution of 29c (0.38 g, 1.84 mmol) in THF (15 mL) was added CDI(2.1 mol eq, 0.63 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×25 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (yellow oil,0.62 g, quantitative yield). The oil obtained was dissolved in DMF (20mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.21 g), then themixture obtained was heated at 100° C. overnight. The solvent wasremoved at reduced pressure and the residue was purified bychromatography (1:1 EtOAc:petroleum ether) to afford the product as awhite solid (0.1 g, 14% Yield). ¹HNMR (DMSO, 400 MHz) δ 3.96 (s, 3H),4.29 (d, 2H, J=6), 4.62 (s, 2H), 6.46 (dd, 1H, J=2), 6.80 (t, 1H, J=8),7.34 (bt, 1H), 7.51 (d, 1H, J=8), 7.72 (m, 2H), 8.24 (s, 1H), 10.66 (s,1H). [M⁺¹] 396.99 (C₁₇H₁₅F₃N₄O₄ requires 396.32).

Example 831-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-pyridyl]methyl]urea

To a solution of triphosgene (0.07 g, 0.37 mol eq) in anh. CH₂Cl₂ (10mL) was slowly added the amine 1f (0.2 g, 1 mmol) solubilized in CH₂Cl₂(10 mL) and DIEA (2.2 mol eq, 0.4 mL). After the addition was completed,the reaction mixture was stirred at room temp. for 15 min. Then the[5-(trifluoromethyl)-2-pyridyl]methanamine (1 mol eq, 0.18 g)solubilized in CH₂Cl₂ (10 mL) and DIEA (2.2 mol eq, 0.4 mL) was added inone portion. The mixture obtained was stirred at room temp. for 12 h.The solvent was removed at reduced pressure, water was added and themixture was extracted with EtOAc (3×20 mL). The recombined organicphases were anhydrified over sodium sulfate and evaporated to dryness.The residue was purified by crystallization from EtOAc to obtain theproduct as yellow solid (0.132 g, 37% Yield). ¹HNMR (DMSO, 400 MHz) δ4.47 (d, 2H, J=6), 4.63 (s, 2H), 6.46 (dd, 1H, J=2), 6.80 (t, 1H, J=8),7.57 m, 2H), 7.72 (dd, 1H, J=2), 8.18 (dd, 1H, J=2), 8.22 (s, 1H), 8.90(m, 1H), 10.66 (s, 1H). [M⁺¹] 366.94 (C₁₆H₁₃F₃N₄O₃ requires 366.29).

Example 841-[(2-isopropoxy-4-methyl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 15)

Preparation of 2-isopropoxy-4-methyl-benzonitrile 30a

The 2-fluoro-4-methyl-benzonitrile (0.8 g, 3.99 mmol) was added in smallportion to a mixture of NaH 60% (4 mol eq, 0.61 g) in isopropanol (30mL). The reaction mixture was heated at 50° C. overnight. The solventwas distilled and water was added to the residue. The aqueous solutionwas extracted with EtOAc (3×25 mL) and the organic phases wereevaporated at reduced pressure to give 30a as a deliquescent white solid(1.09 g, 6.22 mmol). ¹HNMR (DMSO, 200 MHz) δ 1.21 (s, 3H), 1.28 (s, 3H),2.10 (s, 3H), 4.89 (m, 1H), 7.41 (d, 1H), 7.55 (s, 1H), 7.89 (m, 1H).

Preparation of [2-isopropoxy-4-(trifluoromethyl)phenyl]methanamine 31a

The nitrile 30a (1.09 g, 6.22 mmol) was added in small portion to amixture of LiAlH₄ (0.47 g, 2 mol eq) in Et₂O (40 mL) stirred at 0° C.Then the mixture was stirred at room temperature overnight. The excessof LiAlH₄ was decomposed by water addition at 0° C., the solid formedwas filtered, washed with Et₂O and the filtrate was separated. Theorganic phase was anhydrified over Na₂SO₄ and evaporated to dryness toobtain 31a as yellow oil (0.95 g, 85% Yield) used without furtherpurification.

Preparation of1-[(2-isopropoxy-4-methyl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

To a solution of 31a (0.95 g, 5.20 mmol) in THF (20 mL) was added CDI(2.1 mol eq, 1.80 g) and the mixture was heated at 70° C. for 6 h. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×35 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (yellow oil,1.4 g, 97% yield). The oil obtained (0.7 g, 2.56 mmol) was dissolved inDMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.24 g),then the mixture obtained was heated at 100° C. overnight. The solventwas removed at reduced pressure and the residue was purified bychromatography (1:1 EtOAc:Petroleum ether) to obtain the product as awhite solid (0.104 g, 24% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.26 (s, 3H),1.29 (s, 3H), 2.26 (s, 3H), 4.18 (d, 2H, J=6), 4.60 (m, 3H), 6.44 (dd,1H), 6.76 (m, 2H), 6.99 (m, 3H), 7.76 (dd, 1H), 8.13 (s, 1H), 10.64 (s,1H). [M⁺¹] 370.00 (C₂₀H₂₃N₃O₄ requires 369.41).

Example 851-[(2-isopropoxy-6-methyl-3-pyridyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 16)

Preparation of 2-isopropoxy-6-methyl-pyridine-3-carbonitrile 32a

The 2-chloro-6-methyl-nicotinonitrile (0.8 g, 5.2 mmol) was added insmall portion to a mixture of NaH 60% (4 mol eq, 0.8 g) in isopropanol(30 mL). The reaction mixture was heated at 50° C. overnight. Thesolvent was distilled and water was added to the residue. The aqueoussolution was extracted with EtOAc (3×30 mL) and the organic phases wereevaporated at reduced pressure to give 32a as a pale yellow deliquescentsolid (1.25 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.24 (s,3H), 1.32 (s, 3H), 2.25 (s, 3H), 5.02 (m, 1H), 7.31 (d, 1H), 7.69 (m,1H).

Preparation of [2-isopropoxy-6-methyl-3-pyridyl]methanamine 33a

The nitrile 32a (1.25 g, 7.12 mmol) solubilized in Et₂O (20 mL) and THF(10 mL) was added in small portion to a mixture of LiAlH₄ (0.54 g, 2 moleq) in Et₂O (50 mL) stirred at 0° C. Then the mixture was stirred atroom temperature overnight. The excess of LiAlH₄ was decomposed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was separated. The organic phase was anhydrified overNa₂SO₄ and evaporated to dryness to obtain 33a as yellow oil (1.14 g,6.35 mmol, 89% Yield) used without further purification.

Preparation of1-[(2-isopropoxy-6-methyl-3-pyridyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

To a solution of 33a (1.14 g, 6.35 mmol) in THF (30 mL) was added CDI(2.1 mol eq, 2.16 g) and the mixture was heated at 70° C. for 6 h. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×35 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (yellow oil,1.61 g, 93% yield). The oil obtained (0.34 g, 1.25 mmol) was dissolvedin DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.20 g),then the mixture obtained was heated at 100° C. overnight. The solventwas removed at reduced pressure and the residue was purified bychromatography (1:1 EtOAc:Petroleum ether) to obtain the product as awhite solid (0.07 g, 21% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.28 (s, 3H),1.31 (s, 3H), 2.34 (s, 3H), 4.14 (d, 2H, J=6), 4.60 (s, 2H), 5.25 (m,1H), 6.48 (dd, 1H), 6.77 (m, 2H), 7.11 (t, 1H), 7.44 (d, 1H, J=8), 7.71(dd, 1H), 8.16 (s, 1H), 10.64 (bs, 1H). [M⁺¹] 370.95 (C₁₉H₂₂N₄O₄requires 370.40).

Example 861-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 14)

To a solution of 29d (0.78 g, 3.5 mmol) in THF (35 mL) was added CDI(2.1 mol eq, 1.21 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×25 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale orangeoil, quantitative yield). The oil obtained (0.46 g) was dissolved in DMF(25 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.2 g), thenthe mixture obtained was heated at 100° C. overnight. The solvent wasremoved at reduced pressure and the residue was purified bychromatography (7:3 EtOAc:petroleum ether) to obtain the product as apale yellow solid (0.12 g, 21% Yield). ¹HNMR (DMSO, 400 MHz) δ 2.84 (s,6H), 4.36 (d, 2H, J=6), 4.62 (s, 2H), 6.49 (dd, 1H), 6.80 (t, 1H), 7.36(m, 2H), 7.73 (m, 2H), 8.20 (s, 1H), 10.66 (bs, 1H). [M⁺¹] 410.02(C₁₈H₁₈F₃N₅O₃ requires 409.36).

Example 871-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea(Scheme 14)

To a solution of2-(1-pyrrolidinyl)-6-(trifluoromethyl)-3-aminomethyl-pyridine 29e (0.58g, 2.3 mmol) in THF (25 mL) was added CDI (2.1 mol eq, 0.77 g) and themixture was heated for 5 h. The reaction mixture was evaporated, waterwas added and the aqueous phase was extracted with EtOAc (3×20 mL). Therecombined organic phases were anhydrified over Na₂SO₄ and evaporated atreduced pressure. The oil obtained (0.51 g, 1.52 mmol) was dissolved inDMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.20 g),then the mixture obtained was heated at 100° C. overnight. The solventwas removed at reduced pressure and the residue was purified bychromatography (1:1 EtoAc:Petroleum ether) to obtain the product as awhite solid (0.12 g, 24% Yield). ¹HNMR (DMSO, 400 MHz) δ 1.89 (m, 4H),3.56 (m, 4H), 4.41 (d, 2H, J=6), 4.61 8s, 2H), 6.46 (dd, 1H, J=2), 6.80(t, 1H, J=8), 7.12 (d, 1H, J=8), 7.25 (t, 1H), 7.70 (m, 2H), 8.17 (bs,1H), 10.66 (bs, 1H). [M⁺¹] 436.03 (C₂₀H₂₀F₃N₅O₃ requires 435.40).

Example 881-[[2-(imidazol-1-yl)-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

Preparation of 2-imidazol-1-yl-4-(trifluoromethyl)benzonitrile

To a suspension of NaH 60% (0.09 g, 3.97 mmol) in DMF (20 mL) at 0° C.was added in one portion 1H-imidazole (2.5 mol eq, 0.61 g). After 10 min2-chloro-4-(trifluoromethyl)-benzonitrile (0.5 mL, 3.61 mmol) was addedand the reaction mixture was heated at 100° C. for 2 h. The reaction wascooled at room temperature, water was added and the aqueous solution wasextracted with EtOAc (3×25 mL). The recombined organic phases were driedover sodium sulfate and evaporated to dryness to give the2-imidazol-1-yl-4-(trifluoromethyl)benzonitrile as pale yellow oil (0.63g, 73% Yield) used for the reduction without further purification.

Preparation of [2-(imidazol-1-yl)-4-(trifluoromethyl)]benzenemethanamine

The nitrile above described (0.63 g, 2.66 mmol) solubilized in Et₂O (20mL) was added in small portion to a mixture of LiAlH₄ (0.202 g, 2 moleq) in Et₂O (20 mL) stirred at 0° C. Then the mixture was stirred atroom temperature overnight. The excess of LiAlH₄ was decomposed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was separated. The organic phase was anhydrified overNa₂SO₄ and evaporated to dryness to obtain[2-(imidazol-1-yl)-4-(trifluoromethyl)]benzenemethanamine as orange oil(0.53 g, 83% Yield). ¹HNMR (DMSO, 200 MHz) δ 4.32 (bs, 2H), 7.23 (s,1H), 7.89 (s, 1H), 8.21 (d, 1H, J=8), 8.41 (m, 1H), 8.94 (dd, 1H, J=2).

Preparation of1-[[2-imidazol-1-yl-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

To a solution of[2-(imidazol-1-yl)-4-trifluoromethyl)]benzenemethanamine (0.53 g, 2.2mmol) in THF (35 mL) was added CDI (2.1 mol eq, 0.75 g) and the mixturewas heated at 70° C. overnight. The reaction mixture was evaporated,water was added and the aqueous phase was extracted with EtOAc (3×25mL). The recombined organic phases were anhydrified over Na₂SO₄ andevaporated at reduced pressure (pale orange oil, quantitative yield).The oil obtained (0.51 g, 1.52 mmol)) was dissolved in DMF (20 mL) andthe bicyclic amine 1f was added (0.8 mol eq, 0.2 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by chromatography (100%EtOAc) to obtain the product as a white solid (0.14 g, 28% Yield). ¹HNMR(DMSO, 400 MHz) δ 4.20 (d, 2H, J=6), 4.62 (s, 2H), 6.46 (dd, 1H, J=2),6.79 (t, 1H, J=8), 7.15 (s, 1H), 7.38 (t, 1H), 7.55 (s, 1H), 7.69 (m,3H), 7.87 (m, 2H), 8.20 (bs, 1H), 10.66 (bs, 1H). [M⁺¹] 432.01(C₂₀H₁₆F₃N₅O₃ requires 431.37).

Example 891-[(4-tert-butylphenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

To a solution of 4-tert-butylbenzylamine (2 mL, 11.36 mmol) in THF (30mL) was added CDI (2.1 mol eq, 3.86 g) and the mixture was heated at 70°C. overnight. The reaction mixture was evaporated, water was added andthe aqueous phase was extracted with EtOAc (3×30 mL). The recombinedorganic phases were anhydrified over Na₂SO₄ and evaporated at reducedpressure (pale yellow oil, quantitative yield). The oil obtained (0.58g, 2.28 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f wasadded (0.8 mol eq, 0.30 g), then the mixture obtained was heated at 100°C. overnight. The solvent was removed at reduced pressure and theresidue was purified by chromatography (1:1 EtOAc:petroleum ether) toobtain the product as a white solid (0.17 g, 27% Yield). ¹HNMR (DMSO,400 MHz) δ 1.26 (s, 9H), 4.24 (d, 2H, J=6), 4.60 (s, 2H), 4.45 (dd, 1H,J=2), 6.81 (t, 1H, J=10), 7.18 (d, 2H, J=8), 7.36 (d, 2H, J=8), 7.76(dd, 1H), 8.06 (bs, 1H), 10.64 (bs, 1H). [M⁺¹] 353.98 (C₂₀H₂₃N₃O₃requires 353.41).

Example 901-[(4-methyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 15)

Preparation of 4-methyl-2-(pyrrolidin-1-yl)-benzonitrile 30b (Scheme 15)

To 2-fluoro-4-methyl-benzonitrile (1.5 g, 11.1 mmol) was addedpyrrolidine (3.67 mL, 4 mol eq) and the mixture was heated in neat at90° C. overnight. The mixture was concentrated, water was added and themixture was extracted with EtOAc (3×30 mL). The recombined organicphases were anhydrified and evaporated to dryness to obtain 30b as paleyellow crystals (2.03 g, 98% yield). ¹HNMR (DMSO, 200 MHz) δ 1.21 (m,4H), 2.10 (m, 4H), 3.89 (s, 3H), 7.31 (d, 1H), 7.45 (s, 1H), 7.79 (m,1H).

Preparation of (4-methyl-2-pyrrolidin-1-yl-phenyl)-methanamine 31b

The nitrile 30b (2.03 g, 10.9 mmol) solubilized in Et₂O (25 mL) wasadded in small portion to a mixture of LiAlH₄ (0.83 g, 2 mol eq) in Et₂O(30 mL) stirred at 0° C. Then the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was decomposed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was separated. The organic phase was anhydrified overNa₂SO₄ and evaporated to dryness to obtain 31b as a pale yellow oil(2.12, quantitative Yield) used without further purification.

Preparation of1-[(4-methyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea

To a solution of 31b (2.1 g, 11 mmol) in THF (50 mL) was added CDI (2.1mol eq, 3.79 g) and the mixture was heated for 5 h. The reaction mixturewas evaporated, water was added and the aqueous phase was extracted withEtOAc (3×30 mL). The recombined organic phases were anhydrified overNa₂SO₄ and evaporated at reduced pressure to obtain a pale yellow oil(3.5 g). One portion of this oil (0.7 g, 2.46 mmol) was dissolved in DMF(20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.25 g), thenthe mixture obtained was heated at 100° C. overnight. The solvent wasremoved at reduced pressure and the residue was purified bychromatography (1:1 EtOAc:petroleum ether) to obtain the product as apale yellow solid (0.30 g, 0.78 mmol, 31% Yield). ¹HNMR (DMSO, 400 MHz)δ 1.87 (m, 4H), 2.23 (s, 3H), 3.10 (m, 4H), 4.26 (d, 2H, J=6), 4.60 (s,2H), 6.44 (dd, 1H), 6.76 (m, 3H), 7.1 (d, 2H), 7.74 (dd, 1H), 8.13 (s,1H), 10.64 (bs, 1H).

Example 911-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 14)

To a solution of 29b (1.21 g, 4.6 mmol) in THF (25 mL) was added CDI(2.1 mol eq, 1.6 g) and the mixture was heated at 70° C. for 6 h. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×30 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (yellow oil,1.17 g, 71% yield). The oil obtained was dissolved in DMF (20 mL) andthe bicyclic amine 1a was added (0.8 mol eq, 0.35 g), then the mixtureobtained was heated at 100° C. overnight. The solvent was removed atreduced pressure and the residue was purified by chromatography (8:2EtOAc:MeOH) to obtain the product as a pale yellow solid (0.23 g, 24%Yield). ¹HNMR (DMSO, 400 MHz) δ 2.33 (s, 6H), 2.83 (t, 2H), 4.30 (d, 2H,J=6), 4.45 (t, 2H, J=6), 4.61 (s, 2H), 6.46 (dd, 1H), 6.80 (t, 1H, J=8),7.36 (t, 1H), 7.47 (d, 1H, J=8), 7.76 (m, 2H), 8.25 (s, 1H), 10.67 (bs,1H).

[M⁺¹] 454.02 (C₂₀H₂₂F₃N₅O₄ requires 453.41).

Example 921-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea(Scheme 13)

To a solution of 27b (1.48 g, 5.64 mmol) in THF (25 mL) was added CDI(2.1 mol eq, 1.92 g) and the mixture was heated at 70° C. overnight. Thereaction mixture was evaporated, water was added and the aqueous phasewas extracted with EtOAc (3×30 mL). The recombined organic phases wereanhydrified over Na₂SO₄ and evaporated at reduced pressure (pale yellowoil, 1.91 g, 95% yield). The oil obtained (0.95 g, 2.68 mmol) wasdissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 moleq, 0.35 g), then the mixture obtained was heated at 100° C. overnight.The solvent was removed at reduced pressure and the residue was purifiedby chromatography (8:2 EtOAc:MeOH) to obtain the product as a whitesolid (0.33 g, 35% Yield). ¹HNMR (DMSO, 400 MHz) δ 2.27 (s, 6H), 2.71(t, 2H), 4.20 (t, 2H), 4.32 (d, 2H, J=6), 4.62 (s, 2H), 6.50 (dd, 1H),6.80 (t, 1H), 7.29 (m, 3H), 7.40 (d, 1H), 7.70 (dd, 1H), 8.18 (s, 1H),10.65 (bs, 1H). [M⁺¹] 452.91 (C₂₁H₂₃F₃N₄O₄ requires 452.43).

Pharmacology

Drugs and reagents were obtained from the indicated companies:capsaicin, ionomycin, laminin, poly-L-lysine, collagenase, trypsin,L-glutamine, penicillin/streptomycin, DMEM, HBSS, mouse-NGF-7S, ARA-C,HEPES, Tween80, Complete Freund's Adjuvant (CFA) and BSA (Sigma, Italy);FBS and HS (Gibco, Italy); Fura-2-AM-ester (Vinci-Biochem, Italy) andMethylcellulose (Fluka, Switzerland). The stock concentration (10 mM) ofcapsaicin, Fura-2-AM-ester, ionomycin and all tested compounds wereprepared in 100% DMSO.

Ca²⁺ Fluorescence Measurements in Cultured Rat Dorsal Root

Male SD rats (˜50 g, Charles River, Italy) were terminally anaesthetizedand decapitated. Dorsal root ganglia were removed and placed in coldHank's balanced salt solution (HBSS) before being transferred tocollagenase (2 mg/ml) and trypsin (1 mg/ml) for 35 min at 37° C. Theganglia, placed in cold DMEM supplemented with 10% fetal bovine serum,10% horse serum, 2 mM L-glutamine, 100 U/ml penicillin and 100 μg/mlstreptomycin, were dissociated in single cells by several passagesthrough a series of syringe needles (23G down to 25G). The medium andthe ganglia were filtered to remove debris, topped up with 4 ml of DMEMmedium and centrifuged (1100 rpm for 6 min). The final cell pellet wasre-suspended in DMEM medium [supplemented with 100 ng/ml mouse NerveGrowth Factor (mouse-NGF-7S) and cytosine-β-D-arabinofuranoside freebase (ARA-C) 2.5 μM]. The cells were plated on poly-L-lysine (8.3 μM)-and laminin (5 μM)-coated 25 mm glass cover slips and kept for 2 days at37° C. in a humidified incubator gassed with 5% CO₂ and air, thentreated with Fura-2-AM-ester (5 μM) in a Ca²⁺ buffer solution having thefollowing composition (mM): CaCl₂ 1.4, KCl 5.4, MgSO₄ 0.4, NaCl 135,D-glucose 5, HEPES 10 with BSA (0.1%), at pH 7.4, for 40 min at 37° C.The cells were then washed twice with the Ca²⁺ buffer solution andtransferred to a chamber on the stage of a Nikon eclipse TE300microscope. Fura-2-AM-ester was excited at 340 nM and 380 nM to indicaterelative [Ca²⁺ ]_(i) changes by the F₃₄₀/F₃₈₀ ratio recorded with adynamic image analysis system (Laboratory Automation 2.0, RCS, Florence,Italy) and the cells were allowed (at least 10 min) to attain a stablefluorescence before beginning the experiment. A calibration curve wasset up using buffer containing Fura-2-AM-ester and determinantconcentrations of free Ca²⁺. This curve was then used to convert thedata obtained from the F₃₄₀/F₃₈₀ ratio to [Ca²⁺]_(i) (nM).

All exemplified compounds were tested at the concentration of 300 nMagainst the calcium uptake induced by 30 nM capsaicin. For selectedmolecules, the IC₅₀ value was calculated.

CFA-Induced Thermal Hyperalgesia in Rats

This method was used for the determination of acute nociceptive thermalthreshold and combines a chemical stimulus and heat for measuring painsensitivity. Male SD rats (Charles River, Italy) weighing 100 to 250 gr.were used. Anti-hyperalgesic effects were investigated by using theHargreaves' test. Complete Freund's Adjuvant (CFA; Sigma, USA) was usedto induce thermal hyperalgesia. CFA contains killed Mycobacteriumtuberculosis and is designed to provide continuous release of antigensnecessary for stimulating a strong, persistent immune response. Thiseffect causes the reduction of the hind paw withdrawal response latencyinduced by heat during the Hargreaves' test. Thermal stimulation wasperformed 30, 60, 120 and 180 (240 min only if needed) minutes after theoral administration of the antagonists. During the CFA-induced thermalhyperalgesia experiments two different solubilization protocols wereused: when items presented an amino group, a pH=2 aqueous solution ofHCl and 2.5% Tween80 was used; otherwise molecules were suspended in0.5% Methocel and 2.5% Tween80. Compounds were orally administrated (30μmol/kg/10 ml) to rats 24 hours after the CFA treatment. CFA wasinjected into the plantar surface of a rat's hind paw at a fixed dose of50 μl by the use of a micro syringe.

CFA-Induced Tactile Allodynia in Rats

Male SD rats (Charles River, Italy) weighing 100 to 250 g were put intoa clean plastic cage on an elevated glass plate for 30 min before thetest. This lets the animals accommodate to their new environment beforetesting. Complete Freund's adjuvant (CFA, 50 μl) was injected into theplantar surface of the right hind paw. Tactile stimulation was performedwith von Frey filaments (from 0.07 to 26 g). All antagonists were orallyadministered 22 hours after to the CFA administration. Von Freyfilaments were applied 30, 60, 120, 180, 240, 300 and 360 min aftercompound administrations. Median 50% (EG₅₀) threshold of von Freyfilaments was calculated by using the up-down method as previouslydescribed. All tested compounds were suspended in 0.5% Methocel and 2.5%Tween80 and orally administrated (30 μmol/kg/10 ml) to rats by gavage 24hours after the CFA treatment. CFA was injected into the plantar surfaceof a rat's hind paw at a fixed dose of 50 μl by the use of a microsyringe.

Rectal Temperature Measurements in Rats

Body temperature was measured by a digital thermometer inserted at adepth of approximately 3 cm into the rectum of each animal (male SDrats, Charles River, Italy, 100 to 250 g). A pre-dose value of bodytemperature was measured prior to the administration of the testsubstance or vehicles. Animals were distributed among groups by themanual method to achieve the almost same mean values of body temperatureof the groups based on the pre-dose value. All compounds were dissolvedin 6% DMSO/6% Tween80 and then intraperitoneally (10 μmol/Kg/5 ml)administrated to rats.

CCI-Induced Mechanical Hyperalgesia

Male SD rats (Charles River, Italy) weighing 250 g were anaesthetizedwith sodium pentobarbital (60 mg/kg, intraperitoneal (i.p.), 0.1 ml/10g) and, under a dissecting microscope, the right common sciatic nervewas exposed at the level of the mid thigh and, proximal to thetrifurcation of the nerve; four ligatures (4/0 chromic silk, Ethicon)were loosely tied around it, at about 0.5 mm spacing, until theyelicited a brief twitch in the respective hind, taking care to preserveepineural circulation. Sham-operated animals (sciatic exposure withoutligation) were used as controls. 14 days after the surgery, mechanicalhyperalgesia was assessed using an analgesimeter (Ugo Basile, Italy,Randall-Selitto analgesic apparatus). This device generated a mechanicalforce on the affected paw and the nociceptive threshold was defined asthe force (in g) at which the rat withdraws the paw (with a cut-off of450 g). Two baseline measurement values were obtained 75 and 45 minbefore the actual test. After the second baseline measurement, animalswere randomly allocated to the different treatment groups. Paw pressuretest was performed 0, 75, 120, 165, 210 and 300 min after the oraladministration of the compounds. All tested compounds were orallyadministrated (30 μmol/kg/10 ml) to rats by gavage.

RESULTS

Ca²⁺ Fluorescence Measurements in Cultured Rat Dorsal Root GangliaNeurons

Capsaicin (0.3 μM) caused an increase in [Ca²⁺] in the vast majority(95%) of dorsal root ganglia neurons, which were thereby identified asTRPV1 expressing neurons. All synthesized derivatives were tested andall were able to inhibit the calcium uptake and several compoundsexhibited more than 80% inhibition, e.g. compounds of Examples 1, 3, 4,5, 6, 10, 11, 12, 13, 16, 19, 23, 31, 32, 35, 36, 39, 41, 45, 46, 47,48, 51, 53, 67, 68, 69, 70, 71, 74, 75, 78, 80, 81, 82, 86, 87 and 89.Among them, derivatives such as compounds of Examples 4, 5, 6, 13, 19,31, 36, 39, 45, 46, 47, 48, 51, 52, 53, 67, 70, 71, 74, 75, 78, 80, 81,86 and 87, appeared the most potent TRPV1 antagonists exhibiting acomplete abolition of capsaicin response (around 100%) at 300 nM.

The IC₅₀ values of the compounds of Examples 4, 5, 6, 12, 13, 31, 46,47, 48, 51, 73, 75 and 78 calculated against capsaicin-evoked [Ca²⁺]_(i)mobilization were 4.07 nM, 1 nM, 0.51 nM, 6 nM, 1.8 nM, 1.9 nM, 3 nM,0.7 nM, 0.13 nM, 1.8, 0.1 nM, 0.84 nM and 0.61, respectively.

Tables 1, 2 and 3 describe the calcium assay data for all exemplifiedcompounds of formula IA-C, ID-E and IF-H, respectively.

TABLE 1 Compound % inhibition IC50 of Example at 300 nM (nM) Example 184 Example 2 28 Example 3 93 Example 4 100 4.07 Example 5 100 1 Example6 95 0.51 Example 7 33 Example 8 2 Example 9 18 Example 10 89 79 Example11 82 12 Example 12 88 6 Example 13 96 1.8 Example 14 32 Example 15 54Example 16 86 Example 17 44 Example 18 54 Example 19 99 Example 20 18Example 21 79 Example 22 48 Example 23 82 108 Example 24 40 Example 2540 Example 26 55 Example 27 45 Example 28 40 Example 29 8 Example 30 44Example 31 100 1.9 Example 32 93 Example 33 16 Example 34 19 Example 3590 Example 36 100 Example 39 98 9.5 Example 40 52 Example 41 88 Example42 30 Example 43 23 Example 44 47 Example 45 100 Example 46 94 3 Example47 100 0.7 Example 48 100 0.13 Example 49 68 Example 50 52 Example 51100 0.1 Example 52 98 Example 53 90 Example 54 55 Example 66 71 Example67 100 20 Example 68 93 Example 69 80 92 Example 70 98 Example 71 100 12Example 72 40 6 Example 73 25 1.8 Example 74 100 Example 75 100 0.84Example 76 40 Example 77 71 Example 78 100 0.61 Example 79 54 Example 8095 Example 81 100 Example 82 90 54 Example 83 57 Example 84 61 Example85 79 Example 86 100 17 Example 87 100 9 Example 88 75 Example 89 9219.8 Example 90 47 Example 91 40 Example 92 12

TABLE 2 Compound % inhibition of Example at 300 nM Example 55 10 Example56 31 Example 57  7 Example 58 43

TABLE 3 Compound % inhibition of Example at 300 nM Example 59  5 Example60  8 Example 61 15 Example 62  8 Example 63 79 Example 64 65 Example 65 4

CFA-Induced Thermal Hyperalgesia in Rats

The more potent antagonists were orally administered at 30 μmol/kg. Thecompound of Example 51 was able to counteract the CFA effects producinga maximal reversal activity of 30%. In contrast, the compounds ofExamples 5, 12, 13, 23, 31, 46, 47, 48, 49 produced a sustainedanti-hyperalgesic effect showing 53%, 65%, 60%, 46%, 47%, 50%, 46%, 45%and 52% of reversion respectively.

CFA-Induced Tactile Allodynia in Rats

The compound of Example 5 (30 μmol/kg, oral) significantly reversedCFA-induced tactile allodynia (60% of reversal) up to 240 minpost-treatment while the same dose of the compound of Example 51provoked 61% of reversal but showed a shorter duration. The compound ofExample 12 produced a statistically significant anti-hyperalgesic effectup to 300 min post-treatment. (62% of reversal). The compound of example49 joined 72% of reversal.

Rectal Temperature Measurement in Rats

None of the more potent compounds affected rectal rat body temperatureapart from the compound of Example 31 which induced hypothermia (−1.5°C.), and the compound of Example 46 which caused hyperthermia. (+0.8°C.).

CCI-Induced Mechanical Hyperalgesia

All selected compounds exhibited a significant anti-hyperalgesic effect.Particularly, derivatives the compounds of Examples 1, 5, 6, 31, 13, 46and 49 induced relevant and long lasting anti-hyperalgesic activity.Moreover, all the above mentioned compounds produced at least 80%reversal of hyperalgesia within the first 2 hours of experimentation.

REFERENCES

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The invention claimed is:
 1. A compound selected from the groupconsisting of:1-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea,1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4] oxazin-5-yl)urea,1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-5-yl)urea,1-(4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(2-(dimethylamino)-4-(trifluoromethyl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(4-(trifluoromethyl)-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(4-(trifluoromethyl)-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(4-chlorobenzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(4-chloro-2-(dimethylamino)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(4-chloro-2-(pyrrolidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4] oxazin-8-yl)urea,1-(4-chloro-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(4-methyl-2-(piperidin-1-yl)benzyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4] oxazin-8-yl)urea,1-(6-chloropyridin-3-yl)methyl)-3-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-8-yl)urea,1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-furyl]methyl]urea,1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[6-(trifluoromethyl)-3-pyridyl]methyl]urea,1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[2-(1-piperidyl)-6-(trifluoromethyl)-3-pyridyl]methylurea,1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-(p-tolylmethyl)urea,1-[[6-methyl-2-(1-piperidyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[[2-isopropoxy-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[[2-methoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[5-(trifluoromethyl)-2-pyridyl]methyl]urea,1-[(2-isopropoxy-4-methyl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[(2-isopropoxy-6-methyl-3-pyridyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[[2-dimethylamino-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-(3-oxo-4H-1,4-benzoxazin-8-yl)-3-[[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]methyl]urea,1-[[2-(imidazol-1-yl)-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[(4-tert-butylphenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[(4-methyl-2-pyrrolidin-1-yl-phenyl)methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,1-[[2-(2-dimethylaminoethoxy)-6-(trifluoromethyl)-3-pyridyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea,and1-[[2-(2-dimethylaminoethoxy)-4-(trifluoromethyl)phenyl]methyl]-3-(3-oxo-4H-1,4-benzoxazin-8-yl)urea.2. A composition comprising the compound of claim 1; and apharmaceutically acceptable carrier.
 3. A method of treating a diseaseor condition ameliorated by inhibition of the vanilloid receptor TRPV1selected from: pain associated with burns, post-operative pain,osteoarthritis, rheumatoid arthritis, headaches, dental pain, pelvicpain, migraine, mastalgia, visceral pain, neuropathy, irritable bowelsyndrome, gastro-esophageal reflux disease, Crohn's disease, asthma,chronic obstructive pulmonary disease, cough, urinary incontinence,urinary bladder hypersensitiveness, psoriasis, dermatitis, myocardialischemia, hirsutism, alopecia, rhinitis, pancreatitis, vulvodynia, dryeye, anxiety or obesity, the method comprising administering aneffective amount of a compound of claim 1, to a subject in need thereof.4. A method of treating Dry Eye comprising administering an effectiveamount of a compound of claim 1, to a subject in need thereof.
 5. Themethod of claim 3, wherein said effective amount comprises from about0.1 mg to 2000 mg/day.
 6. The method of claim 3, wherein said effectiveamount comprises from about 5 mg to 100 mg/day.
 7. A compound having thefollowing structure: